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How anti-CD44 antibodies fight AML
Image by Lance Liotta
New research appears to explain how antibodies that target CD44 fight acute myeloid leukemia (AML).
Previous research showed that anti-CD44 antibodies inhibit proliferation and induce differentiation in AML, but it wasn’t clear how or why this happens.
The new study suggests anti-CD44 antibodies work by inhibiting 2 “major players” of the PI3K/Akt/mTOR pathway—mTORC1 and mTORC2.
Jasmeen Merzaban, PhD, of King Abdullah University of Science and Technology in Thuwal, Saudi Arabia, and her colleagues described this discovery in a letter to Leukemia.
The researchers tested an anti-CD44 antibody known as A3D8 in cell lines representing different AML subtypes (HL60, THP-1, and KG1a) as well as a mouse model of AML.
In these experiments, A3D8 inhibited proliferation and induced differentiation in AML cells. This was accompanied by a decrease in phosphorylation of the mTORC1 and mTORC2 complexes, which was strongly correlated with inhibition of the PI3K/Akt pathway.
The researchers said this finding is important because a complete shutdown of mTOR signaling is probably needed to disrupt the multiple feedback loops that can fuel AML growth, and drugs that only inhibit one of these complexes have, in the past, failed to demonstrate a therapeutic benefit for patients with AML.
“A growing body of evidence suggests that a broader inhibitor would result in a more potent therapeutic effect,” Dr Merzaban said.
She and her colleagues believe an anti-CD44 antibody like A3D8 might just be that type of inhibitor.
They also noted that A3D8 was able to induce differentiation in different subtypes of AML and did not seem to present any toxicity issues.
“We show that the anti-CD44 antibody used for our studies had no effect on normal blood cells,” said Samah Gadhoum, PhD, a research scientist in Dr Merzaban’s lab.
“However, more work is needed to carefully determine the effect of these antibodies on other cells and other cellular functions within the body.”
The researchers are now conducting follow-up experiments, but they believe their results support the use of anti-CD44 antibodies to treat different types of AML. 
Image by Lance Liotta
New research appears to explain how antibodies that target CD44 fight acute myeloid leukemia (AML).
Previous research showed that anti-CD44 antibodies inhibit proliferation and induce differentiation in AML, but it wasn’t clear how or why this happens.
The new study suggests anti-CD44 antibodies work by inhibiting 2 “major players” of the PI3K/Akt/mTOR pathway—mTORC1 and mTORC2.
Jasmeen Merzaban, PhD, of King Abdullah University of Science and Technology in Thuwal, Saudi Arabia, and her colleagues described this discovery in a letter to Leukemia.
The researchers tested an anti-CD44 antibody known as A3D8 in cell lines representing different AML subtypes (HL60, THP-1, and KG1a) as well as a mouse model of AML.
In these experiments, A3D8 inhibited proliferation and induced differentiation in AML cells. This was accompanied by a decrease in phosphorylation of the mTORC1 and mTORC2 complexes, which was strongly correlated with inhibition of the PI3K/Akt pathway.
The researchers said this finding is important because a complete shutdown of mTOR signaling is probably needed to disrupt the multiple feedback loops that can fuel AML growth, and drugs that only inhibit one of these complexes have, in the past, failed to demonstrate a therapeutic benefit for patients with AML.
“A growing body of evidence suggests that a broader inhibitor would result in a more potent therapeutic effect,” Dr Merzaban said.
She and her colleagues believe an anti-CD44 antibody like A3D8 might just be that type of inhibitor.
They also noted that A3D8 was able to induce differentiation in different subtypes of AML and did not seem to present any toxicity issues.
“We show that the anti-CD44 antibody used for our studies had no effect on normal blood cells,” said Samah Gadhoum, PhD, a research scientist in Dr Merzaban’s lab.
“However, more work is needed to carefully determine the effect of these antibodies on other cells and other cellular functions within the body.”
The researchers are now conducting follow-up experiments, but they believe their results support the use of anti-CD44 antibodies to treat different types of AML.
Image by Lance Liotta
New research appears to explain how antibodies that target CD44 fight acute myeloid leukemia (AML).
Previous research showed that anti-CD44 antibodies inhibit proliferation and induce differentiation in AML, but it wasn’t clear how or why this happens.
The new study suggests anti-CD44 antibodies work by inhibiting 2 “major players” of the PI3K/Akt/mTOR pathway—mTORC1 and mTORC2.
Jasmeen Merzaban, PhD, of King Abdullah University of Science and Technology in Thuwal, Saudi Arabia, and her colleagues described this discovery in a letter to Leukemia.
The researchers tested an anti-CD44 antibody known as A3D8 in cell lines representing different AML subtypes (HL60, THP-1, and KG1a) as well as a mouse model of AML.
In these experiments, A3D8 inhibited proliferation and induced differentiation in AML cells. This was accompanied by a decrease in phosphorylation of the mTORC1 and mTORC2 complexes, which was strongly correlated with inhibition of the PI3K/Akt pathway.
The researchers said this finding is important because a complete shutdown of mTOR signaling is probably needed to disrupt the multiple feedback loops that can fuel AML growth, and drugs that only inhibit one of these complexes have, in the past, failed to demonstrate a therapeutic benefit for patients with AML.
“A growing body of evidence suggests that a broader inhibitor would result in a more potent therapeutic effect,” Dr Merzaban said.
She and her colleagues believe an anti-CD44 antibody like A3D8 might just be that type of inhibitor.
They also noted that A3D8 was able to induce differentiation in different subtypes of AML and did not seem to present any toxicity issues.
“We show that the anti-CD44 antibody used for our studies had no effect on normal blood cells,” said Samah Gadhoum, PhD, a research scientist in Dr Merzaban’s lab.
“However, more work is needed to carefully determine the effect of these antibodies on other cells and other cellular functions within the body.”
The researchers are now conducting follow-up experiments, but they believe their results support the use of anti-CD44 antibodies to treat different types of AML.
Donor NK cells elicited complete remissions in four of nine AML patients
Four of nine acute myeloid leukemia patients went into complete remission – and a fifth responded – after being transfused with donor natural killer cells in a phase I study from Washington University in St. Louis.
The natural killer (NK) cells had been differentiated into “memorylike” NK cells by brief exposure to interleukin (IL) 12, 15, and 18 prior to transfusion. Although NK cells have traditionally been considered part of the innate immune system, it’s become clear recently that they have some adaptive abilities. The cytokine exposure in the St. Louis study seemed, in a sense, to train NK cells to remember and attack acute myeloid leukemia (AML).
The treated cells had enhanced interferon gamma production and cytotoxicity against AML cells in vitro. Once in the patients, they “proliferated extensively” and demonstrated robust responses against leukemia targets. Preactivation of NK cells with IL-12, IL-15, and IL-18 promotes “potent antileukemia functionality in vitro and in vivo and thus represent[s] a promising immunotherapy strategy for AML,” said investigators led by Rizwan Romee, MD, of the oncology division and clinical director of the haploidentical transplant program at Washington University (Sci Transl Med. 2016 Sep. 21. doi: 10.1126/scitranslmed.aaf2341).
NK cell therapy is an emerging treatment for AML, but it’s been unclear, at least until now, how best to maximize the cells’ anti-AML effect before transfer.
Prior studies have tried IL-2 or IL-15 overnight, which does increase NK cell functional capacity, but the effect is rapidly lost after transfer into patients.
That didn’t seem to be much of a problem when NK cells were differentiated into memorylike cells. “The longer-lasting increase in functional capacity ... combined with improved AML recognition, [enhanced] in vivo expansion and antileukemia responses, result[ed] in a several week ‘window of opportunity’ to attack AML blasts.” the authors said.
For safety, the initial cell dose was a tenth or twentieth of the typical adoptive NK cell dose. Even so, the memorylike cells consistently expanded to become greater than 90% of blood and most of bone marrow NK cells, which was “remarkable,” they said.
The National Cancer Institute and others funded the work. The authors had no disclosures.
Four of nine acute myeloid leukemia patients went into complete remission – and a fifth responded – after being transfused with donor natural killer cells in a phase I study from Washington University in St. Louis.
The natural killer (NK) cells had been differentiated into “memorylike” NK cells by brief exposure to interleukin (IL) 12, 15, and 18 prior to transfusion. Although NK cells have traditionally been considered part of the innate immune system, it’s become clear recently that they have some adaptive abilities. The cytokine exposure in the St. Louis study seemed, in a sense, to train NK cells to remember and attack acute myeloid leukemia (AML).
The treated cells had enhanced interferon gamma production and cytotoxicity against AML cells in vitro. Once in the patients, they “proliferated extensively” and demonstrated robust responses against leukemia targets. Preactivation of NK cells with IL-12, IL-15, and IL-18 promotes “potent antileukemia functionality in vitro and in vivo and thus represent[s] a promising immunotherapy strategy for AML,” said investigators led by Rizwan Romee, MD, of the oncology division and clinical director of the haploidentical transplant program at Washington University (Sci Transl Med. 2016 Sep. 21. doi: 10.1126/scitranslmed.aaf2341).
NK cell therapy is an emerging treatment for AML, but it’s been unclear, at least until now, how best to maximize the cells’ anti-AML effect before transfer.
Prior studies have tried IL-2 or IL-15 overnight, which does increase NK cell functional capacity, but the effect is rapidly lost after transfer into patients.
That didn’t seem to be much of a problem when NK cells were differentiated into memorylike cells. “The longer-lasting increase in functional capacity ... combined with improved AML recognition, [enhanced] in vivo expansion and antileukemia responses, result[ed] in a several week ‘window of opportunity’ to attack AML blasts.” the authors said.
For safety, the initial cell dose was a tenth or twentieth of the typical adoptive NK cell dose. Even so, the memorylike cells consistently expanded to become greater than 90% of blood and most of bone marrow NK cells, which was “remarkable,” they said.
The National Cancer Institute and others funded the work. The authors had no disclosures.
Four of nine acute myeloid leukemia patients went into complete remission – and a fifth responded – after being transfused with donor natural killer cells in a phase I study from Washington University in St. Louis.
The natural killer (NK) cells had been differentiated into “memorylike” NK cells by brief exposure to interleukin (IL) 12, 15, and 18 prior to transfusion. Although NK cells have traditionally been considered part of the innate immune system, it’s become clear recently that they have some adaptive abilities. The cytokine exposure in the St. Louis study seemed, in a sense, to train NK cells to remember and attack acute myeloid leukemia (AML).
The treated cells had enhanced interferon gamma production and cytotoxicity against AML cells in vitro. Once in the patients, they “proliferated extensively” and demonstrated robust responses against leukemia targets. Preactivation of NK cells with IL-12, IL-15, and IL-18 promotes “potent antileukemia functionality in vitro and in vivo and thus represent[s] a promising immunotherapy strategy for AML,” said investigators led by Rizwan Romee, MD, of the oncology division and clinical director of the haploidentical transplant program at Washington University (Sci Transl Med. 2016 Sep. 21. doi: 10.1126/scitranslmed.aaf2341).
NK cell therapy is an emerging treatment for AML, but it’s been unclear, at least until now, how best to maximize the cells’ anti-AML effect before transfer.
Prior studies have tried IL-2 or IL-15 overnight, which does increase NK cell functional capacity, but the effect is rapidly lost after transfer into patients.
That didn’t seem to be much of a problem when NK cells were differentiated into memorylike cells. “The longer-lasting increase in functional capacity ... combined with improved AML recognition, [enhanced] in vivo expansion and antileukemia responses, result[ed] in a several week ‘window of opportunity’ to attack AML blasts.” the authors said.
For safety, the initial cell dose was a tenth or twentieth of the typical adoptive NK cell dose. Even so, the memorylike cells consistently expanded to become greater than 90% of blood and most of bone marrow NK cells, which was “remarkable,” they said.
The National Cancer Institute and others funded the work. The authors had no disclosures.
FROM SCIENCE TRANSLATIONAL MEDICINE
Targeting a protein receptor to treat AML, other diseases
Researchers say they have determined the 3-dimensional, atomic structure of GPR56, an adhesion G protein-coupled receptor (aGPCR) linked to the development of several diseases, including acute myeloid leukemia (AML).
The team also engineered a molecule that can turn off GPR56, laying the groundwork for the development of treatments that target diseases mediated by GPR56 and other aGPCRs.
“Given the complicated biology mediated by aGPCRs, particularly in neurodevelopment, we believe our work will pave the way for future studies investigating the molecular details of these important processes, bringing us closer to the ultimate goal of combatting diseases influenced by aGPCRs,” said study author Gabriel Salzman, an MD/PhD student at the University of Chicago in Illinois.
Salzman and his colleagues detailed their work in the journal Neuron.
Over the past several years, researchers have discovered that aGPCRs play a range of biological roles, many of which are closely linked to human diseases.
aGPCRs are characterized by the presence of a large segment that sticks out into the extracellular space. However, a structural foundation for understanding the function of these extracellular regions has been lacking. And researchers didn’t know if these regions could be targeted for therapeutic intervention.
The focus of the current study is GPR56 (also known as ADGRG1), an aGPCR that has established biological roles in muscle cell development, neurodevelopment, and several cancers, including AML.
The researchers engineered a monobody molecule that binds to the extracellular region of GPR56 and causes intracellular signaling to decrease. They said this establishes that it’s possible to change the function of aGPCRs by targeting their extracellular regions with pharmaceuticals.
The team also determined the structure of the entire extracellular region of GPR56 at an atomic level, the first such structural description of any aGPCR. In doing so, they identified a unique protein domain called PLL, which, if deleted, corresponds to a naturally occurring variant of GPR56.
The researchers went on to show that deleting the PLL domain led to increased signaling, further supporting the concept that extracellular regions govern cell signaling.
Bioinformatics analysis also revealed a particular position in the PLL domain that is highly conserved across species, often a telltale sign of biological importance.
The researchers believe that understanding the biological roles played by aGPCR extracellular regions will give scientists more tools to develop treatments for diseases influenced by these protein receptors.
For example, recent studies have shown that AML therapy may benefit from GPR56 inhibition. And this study suggests a monobody like the one created by Salzman’s team might be useful in that respect.
“Our discovery that aGPCR extracellular regions regulate function in a multifaceted and complex manner provides important guidelines for developing therapeutics for diverse diseases in which aGPCRs play important roles,” Salzman said.
Researchers say they have determined the 3-dimensional, atomic structure of GPR56, an adhesion G protein-coupled receptor (aGPCR) linked to the development of several diseases, including acute myeloid leukemia (AML).
The team also engineered a molecule that can turn off GPR56, laying the groundwork for the development of treatments that target diseases mediated by GPR56 and other aGPCRs.
“Given the complicated biology mediated by aGPCRs, particularly in neurodevelopment, we believe our work will pave the way for future studies investigating the molecular details of these important processes, bringing us closer to the ultimate goal of combatting diseases influenced by aGPCRs,” said study author Gabriel Salzman, an MD/PhD student at the University of Chicago in Illinois.
Salzman and his colleagues detailed their work in the journal Neuron.
Over the past several years, researchers have discovered that aGPCRs play a range of biological roles, many of which are closely linked to human diseases.
aGPCRs are characterized by the presence of a large segment that sticks out into the extracellular space. However, a structural foundation for understanding the function of these extracellular regions has been lacking. And researchers didn’t know if these regions could be targeted for therapeutic intervention.
The focus of the current study is GPR56 (also known as ADGRG1), an aGPCR that has established biological roles in muscle cell development, neurodevelopment, and several cancers, including AML.
The researchers engineered a monobody molecule that binds to the extracellular region of GPR56 and causes intracellular signaling to decrease. They said this establishes that it’s possible to change the function of aGPCRs by targeting their extracellular regions with pharmaceuticals.
The team also determined the structure of the entire extracellular region of GPR56 at an atomic level, the first such structural description of any aGPCR. In doing so, they identified a unique protein domain called PLL, which, if deleted, corresponds to a naturally occurring variant of GPR56.
The researchers went on to show that deleting the PLL domain led to increased signaling, further supporting the concept that extracellular regions govern cell signaling.
Bioinformatics analysis also revealed a particular position in the PLL domain that is highly conserved across species, often a telltale sign of biological importance.
The researchers believe that understanding the biological roles played by aGPCR extracellular regions will give scientists more tools to develop treatments for diseases influenced by these protein receptors.
For example, recent studies have shown that AML therapy may benefit from GPR56 inhibition. And this study suggests a monobody like the one created by Salzman’s team might be useful in that respect.
“Our discovery that aGPCR extracellular regions regulate function in a multifaceted and complex manner provides important guidelines for developing therapeutics for diverse diseases in which aGPCRs play important roles,” Salzman said.
Researchers say they have determined the 3-dimensional, atomic structure of GPR56, an adhesion G protein-coupled receptor (aGPCR) linked to the development of several diseases, including acute myeloid leukemia (AML).
The team also engineered a molecule that can turn off GPR56, laying the groundwork for the development of treatments that target diseases mediated by GPR56 and other aGPCRs.
“Given the complicated biology mediated by aGPCRs, particularly in neurodevelopment, we believe our work will pave the way for future studies investigating the molecular details of these important processes, bringing us closer to the ultimate goal of combatting diseases influenced by aGPCRs,” said study author Gabriel Salzman, an MD/PhD student at the University of Chicago in Illinois.
Salzman and his colleagues detailed their work in the journal Neuron.
Over the past several years, researchers have discovered that aGPCRs play a range of biological roles, many of which are closely linked to human diseases.
aGPCRs are characterized by the presence of a large segment that sticks out into the extracellular space. However, a structural foundation for understanding the function of these extracellular regions has been lacking. And researchers didn’t know if these regions could be targeted for therapeutic intervention.
The focus of the current study is GPR56 (also known as ADGRG1), an aGPCR that has established biological roles in muscle cell development, neurodevelopment, and several cancers, including AML.
The researchers engineered a monobody molecule that binds to the extracellular region of GPR56 and causes intracellular signaling to decrease. They said this establishes that it’s possible to change the function of aGPCRs by targeting their extracellular regions with pharmaceuticals.
The team also determined the structure of the entire extracellular region of GPR56 at an atomic level, the first such structural description of any aGPCR. In doing so, they identified a unique protein domain called PLL, which, if deleted, corresponds to a naturally occurring variant of GPR56.
The researchers went on to show that deleting the PLL domain led to increased signaling, further supporting the concept that extracellular regions govern cell signaling.
Bioinformatics analysis also revealed a particular position in the PLL domain that is highly conserved across species, often a telltale sign of biological importance.
The researchers believe that understanding the biological roles played by aGPCR extracellular regions will give scientists more tools to develop treatments for diseases influenced by these protein receptors.
For example, recent studies have shown that AML therapy may benefit from GPR56 inhibition. And this study suggests a monobody like the one created by Salzman’s team might be useful in that respect.
“Our discovery that aGPCR extracellular regions regulate function in a multifaceted and complex manner provides important guidelines for developing therapeutics for diverse diseases in which aGPCRs play important roles,” Salzman said.
Targeting AML’s dependence on fat
New research has revealed a potential treatment strategy for acute myeloid leukemia (AML) and other malignancies that show a preference for metabolizing fat over sugar.
The study suggests the protein prolyl hydroxylase 3 (PHD3) is a key regulator of fatty acid oxidation, and PHD3 expression is low in certain malignancies—particularly AML—but overexpressing PHD3 can have anticancer effects.
Researchers believe this finding might aid the development of therapies that work by starving tumors of their fuel.
“This really represents a new frontier in looking at the metabolism of cancer,” said study author Marcia Haigis, PhD, of Harvard Medical School in Boston, Massachusetts.
“Understanding the molecular handle of this pathway is the first step toward translating the basic work into therapy.”
Dr Haigis and her colleagues described the work in Molecular Cell.
The researchers knew that when cells run low on nutrients, they switch from sugar to fat as their fuel source to sustain function.
When cells have low energy, the protein AMPK targets the enzyme ACC to activate fat oxidation, which helps cells burn fats to make energy. However, when cells have enough resources, they seek to maintain energy balance.
Dr Haigis and her colleagues were searching for precisely how cells turn off fat oxidation and homed in on PHD3. Recent studies had suggested that PHD3 plays a part in cell metabolism, but,
until now, its precise role has remained unclear.
In a series of experiments, Dr Haigis’s team showed that PHD3 suppressed fat-burning by chemically modifying and activating ACC2—a version of the same enzyme responsible for keeping cellular fat-burning in check.
To determine PHD3’s role in cancer, the researchers combed through databases of all human cancers. The team theorized that sugar-craving malignancies would have high levels of PDH3, and cancers that relied on fat for their energy would have low levels.
The researchers found the lowest levels of PHD3 in AML, so they decided to examine the effects of restoring PHD3 in AML cells and a mouse model of the disease.
The experiments showed that restoring PHD3 expression reduces AML potency, and ACC2 is required for the inhibitory effects of PHD3. Overexpressing PHD3 limited fatty acid oxidation via regulation of ACC2, which decreased leukemia cell proliferation and enhanced survival in the mouse model of AML.
Dr Haigis noted that more basic research is needed before this work can move ahead to the clinic, as it’s still unclear why certain cancers depend on fat.
“What do fats provide to tumors that other fuels don’t?” Dr Haigis asked. “That’s one open question, and this is only the first chapter in the story.”
New research has revealed a potential treatment strategy for acute myeloid leukemia (AML) and other malignancies that show a preference for metabolizing fat over sugar.
The study suggests the protein prolyl hydroxylase 3 (PHD3) is a key regulator of fatty acid oxidation, and PHD3 expression is low in certain malignancies—particularly AML—but overexpressing PHD3 can have anticancer effects.
Researchers believe this finding might aid the development of therapies that work by starving tumors of their fuel.
“This really represents a new frontier in looking at the metabolism of cancer,” said study author Marcia Haigis, PhD, of Harvard Medical School in Boston, Massachusetts.
“Understanding the molecular handle of this pathway is the first step toward translating the basic work into therapy.”
Dr Haigis and her colleagues described the work in Molecular Cell.
The researchers knew that when cells run low on nutrients, they switch from sugar to fat as their fuel source to sustain function.
When cells have low energy, the protein AMPK targets the enzyme ACC to activate fat oxidation, which helps cells burn fats to make energy. However, when cells have enough resources, they seek to maintain energy balance.
Dr Haigis and her colleagues were searching for precisely how cells turn off fat oxidation and homed in on PHD3. Recent studies had suggested that PHD3 plays a part in cell metabolism, but,
until now, its precise role has remained unclear.
In a series of experiments, Dr Haigis’s team showed that PHD3 suppressed fat-burning by chemically modifying and activating ACC2—a version of the same enzyme responsible for keeping cellular fat-burning in check.
To determine PHD3’s role in cancer, the researchers combed through databases of all human cancers. The team theorized that sugar-craving malignancies would have high levels of PDH3, and cancers that relied on fat for their energy would have low levels.
The researchers found the lowest levels of PHD3 in AML, so they decided to examine the effects of restoring PHD3 in AML cells and a mouse model of the disease.
The experiments showed that restoring PHD3 expression reduces AML potency, and ACC2 is required for the inhibitory effects of PHD3. Overexpressing PHD3 limited fatty acid oxidation via regulation of ACC2, which decreased leukemia cell proliferation and enhanced survival in the mouse model of AML.
Dr Haigis noted that more basic research is needed before this work can move ahead to the clinic, as it’s still unclear why certain cancers depend on fat.
“What do fats provide to tumors that other fuels don’t?” Dr Haigis asked. “That’s one open question, and this is only the first chapter in the story.”
New research has revealed a potential treatment strategy for acute myeloid leukemia (AML) and other malignancies that show a preference for metabolizing fat over sugar.
The study suggests the protein prolyl hydroxylase 3 (PHD3) is a key regulator of fatty acid oxidation, and PHD3 expression is low in certain malignancies—particularly AML—but overexpressing PHD3 can have anticancer effects.
Researchers believe this finding might aid the development of therapies that work by starving tumors of their fuel.
“This really represents a new frontier in looking at the metabolism of cancer,” said study author Marcia Haigis, PhD, of Harvard Medical School in Boston, Massachusetts.
“Understanding the molecular handle of this pathway is the first step toward translating the basic work into therapy.”
Dr Haigis and her colleagues described the work in Molecular Cell.
The researchers knew that when cells run low on nutrients, they switch from sugar to fat as their fuel source to sustain function.
When cells have low energy, the protein AMPK targets the enzyme ACC to activate fat oxidation, which helps cells burn fats to make energy. However, when cells have enough resources, they seek to maintain energy balance.
Dr Haigis and her colleagues were searching for precisely how cells turn off fat oxidation and homed in on PHD3. Recent studies had suggested that PHD3 plays a part in cell metabolism, but,
until now, its precise role has remained unclear.
In a series of experiments, Dr Haigis’s team showed that PHD3 suppressed fat-burning by chemically modifying and activating ACC2—a version of the same enzyme responsible for keeping cellular fat-burning in check.
To determine PHD3’s role in cancer, the researchers combed through databases of all human cancers. The team theorized that sugar-craving malignancies would have high levels of PDH3, and cancers that relied on fat for their energy would have low levels.
The researchers found the lowest levels of PHD3 in AML, so they decided to examine the effects of restoring PHD3 in AML cells and a mouse model of the disease.
The experiments showed that restoring PHD3 expression reduces AML potency, and ACC2 is required for the inhibitory effects of PHD3. Overexpressing PHD3 limited fatty acid oxidation via regulation of ACC2, which decreased leukemia cell proliferation and enhanced survival in the mouse model of AML.
Dr Haigis noted that more basic research is needed before this work can move ahead to the clinic, as it’s still unclear why certain cancers depend on fat.
“What do fats provide to tumors that other fuels don’t?” Dr Haigis asked. “That’s one open question, and this is only the first chapter in the story.”
Study reveals potential treatment for AML
Compounds that inhibit the metabolic enzyme dihydroorotate dehydrogenase (DHODH) may be effective in treating acute myeloid leukemia (AML), according to preclinical research.
Investigators found that inhibiting DHODH enables myeloid differentiation in AML cells.
In mouse models of AML, treatment with a DHODH inhibitor reduced leukemia burden, decreased leukemia-initiating cell activity, and improved survival.
David Scadden, MD, of Massachusetts General Hospital in Boston, and his colleagues conducted this research and reported the results in Cell.
The research began with the observation that HoxA9, which is normally downregulated during myeloid differentiation, is expressed in roughly 70% of AML patients.
Since no inhibitors of HoxA9 have been identified, Dr Scadden and his colleagues set out to identify compounds that could overcome the differentiation blockade characteristic of AML cells.
The investigators first set up a cellular model of AML by inducing HoxA9 overexpression in mouse myeloid cells genetically engineered to fluoresce if they reached maturity.
The team then screened more than 330,000 small molecules, looking for those that would cause the cells to fluoresce, indicating that the HoxA9-induced differentiation blockade had been overcome.
Only 12 compounds produced the desired result. Eleven of these compounds were found to act by suppressing DHODH, which was not previously known to have a role in myeloid differentiation.
Further experiments showed that DHODH inhibition could induce differentiation in both mouse and human AML cells.
The investigators then tested BRQ, a known DHODH inhibitor, in several mouse models of AML.
Treatment with BRQ led to differentiation, reduced leukemia burden, decreased activity of leukemia-initiating cells, and prolonged survival when compared to treatment with cytarabine and doxorubicin.
“Drug companies tend to be skeptical of the kind of functional screening we used to identify DHODH as a target because it can be complicated and imprecise,” Dr Scadden noted.
“We think that, with modern tools, we may be able to improve target identification, so applying this approach to a broader range of cancers may be justified.”
Compounds that inhibit the metabolic enzyme dihydroorotate dehydrogenase (DHODH) may be effective in treating acute myeloid leukemia (AML), according to preclinical research.
Investigators found that inhibiting DHODH enables myeloid differentiation in AML cells.
In mouse models of AML, treatment with a DHODH inhibitor reduced leukemia burden, decreased leukemia-initiating cell activity, and improved survival.
David Scadden, MD, of Massachusetts General Hospital in Boston, and his colleagues conducted this research and reported the results in Cell.
The research began with the observation that HoxA9, which is normally downregulated during myeloid differentiation, is expressed in roughly 70% of AML patients.
Since no inhibitors of HoxA9 have been identified, Dr Scadden and his colleagues set out to identify compounds that could overcome the differentiation blockade characteristic of AML cells.
The investigators first set up a cellular model of AML by inducing HoxA9 overexpression in mouse myeloid cells genetically engineered to fluoresce if they reached maturity.
The team then screened more than 330,000 small molecules, looking for those that would cause the cells to fluoresce, indicating that the HoxA9-induced differentiation blockade had been overcome.
Only 12 compounds produced the desired result. Eleven of these compounds were found to act by suppressing DHODH, which was not previously known to have a role in myeloid differentiation.
Further experiments showed that DHODH inhibition could induce differentiation in both mouse and human AML cells.
The investigators then tested BRQ, a known DHODH inhibitor, in several mouse models of AML.
Treatment with BRQ led to differentiation, reduced leukemia burden, decreased activity of leukemia-initiating cells, and prolonged survival when compared to treatment with cytarabine and doxorubicin.
“Drug companies tend to be skeptical of the kind of functional screening we used to identify DHODH as a target because it can be complicated and imprecise,” Dr Scadden noted.
“We think that, with modern tools, we may be able to improve target identification, so applying this approach to a broader range of cancers may be justified.”
Compounds that inhibit the metabolic enzyme dihydroorotate dehydrogenase (DHODH) may be effective in treating acute myeloid leukemia (AML), according to preclinical research.
Investigators found that inhibiting DHODH enables myeloid differentiation in AML cells.
In mouse models of AML, treatment with a DHODH inhibitor reduced leukemia burden, decreased leukemia-initiating cell activity, and improved survival.
David Scadden, MD, of Massachusetts General Hospital in Boston, and his colleagues conducted this research and reported the results in Cell.
The research began with the observation that HoxA9, which is normally downregulated during myeloid differentiation, is expressed in roughly 70% of AML patients.
Since no inhibitors of HoxA9 have been identified, Dr Scadden and his colleagues set out to identify compounds that could overcome the differentiation blockade characteristic of AML cells.
The investigators first set up a cellular model of AML by inducing HoxA9 overexpression in mouse myeloid cells genetically engineered to fluoresce if they reached maturity.
The team then screened more than 330,000 small molecules, looking for those that would cause the cells to fluoresce, indicating that the HoxA9-induced differentiation blockade had been overcome.
Only 12 compounds produced the desired result. Eleven of these compounds were found to act by suppressing DHODH, which was not previously known to have a role in myeloid differentiation.
Further experiments showed that DHODH inhibition could induce differentiation in both mouse and human AML cells.
The investigators then tested BRQ, a known DHODH inhibitor, in several mouse models of AML.
Treatment with BRQ led to differentiation, reduced leukemia burden, decreased activity of leukemia-initiating cells, and prolonged survival when compared to treatment with cytarabine and doxorubicin.
“Drug companies tend to be skeptical of the kind of functional screening we used to identify DHODH as a target because it can be complicated and imprecise,” Dr Scadden noted.
“We think that, with modern tools, we may be able to improve target identification, so applying this approach to a broader range of cancers may be justified.”
Studies reveal potential therapeutic targets for resistant AML
Image by NIGMS
A pair of studies suggest the DNA replication checkpoint pathway could be targeted to treat resistant acute myeloid leukemia (AML).
One study indicated that the kinase CHK1, which coordinates the DNA damage response and cell-cycle checkpoint response, might be targeted to overcome cytarabine resistance in AML.
The other study suggested that ATR, a kinase that activates CHK1, and ATM, a second upstream kinase in the DNA damage response, might be therapeutic targets in MLL-rearranged AML.
Both studies were published in Science Sigaling.
Laure David, of La Ligue Contre Le Cancer in Toulouse, France, and colleagues conducted this study.
The researchers integrated gene expression data with survival data from 198 AML patients who were previously treated with cytarabine-based chemotherapy.
The data showed that patients with high expression of CHEK1, the gene that encodes CHK1, had poor survival. And patient cells with high CHK1 abundance were resistant to cytarabine.
However, when the researchers exposed the cells with high CHK1 abundance to the CHK1 inhibitor SCH900776, they observed “reduced clonogenic ability and progression of DNA replication in the presence of cytarabine.”
The team therefore concluded that treatment with a CHK1 inhibitor might overcome resistance to cytarabine-based treatments in AML. They also said that monitoring CHEK1 expression in AML patients could potentially predict outcomes and reveal patients who might benefit from treatment with a CHK1 inhibitor.
The second study was conducted by Isabel Morgado-Palacin, of the Spanish National Cancer Research Center in Madrid, and colleagues.
The researchers investigated ATR, which is the primary sensor of DNA replication stress, and ATM, a kinase that senses DNA double-strand breaks, as possible therapeutic targets in MLL-rearranged AML.
The team found that inhibiting ATR induced chromosomal breakage and death in murine AML-MLL cells in vitro. And inhibiting ATR in vivo reduced the tumor burden and prevented tumors from growing.
The researchers also found that inhibiting ATM prolonged survival in the mouse model of AML-MLL, which suggests that both ATR and ATM might be therapeutic targets in MLL-rearranged AML.
Image by NIGMS
A pair of studies suggest the DNA replication checkpoint pathway could be targeted to treat resistant acute myeloid leukemia (AML).
One study indicated that the kinase CHK1, which coordinates the DNA damage response and cell-cycle checkpoint response, might be targeted to overcome cytarabine resistance in AML.
The other study suggested that ATR, a kinase that activates CHK1, and ATM, a second upstream kinase in the DNA damage response, might be therapeutic targets in MLL-rearranged AML.
Both studies were published in Science Sigaling.
Laure David, of La Ligue Contre Le Cancer in Toulouse, France, and colleagues conducted this study.
The researchers integrated gene expression data with survival data from 198 AML patients who were previously treated with cytarabine-based chemotherapy.
The data showed that patients with high expression of CHEK1, the gene that encodes CHK1, had poor survival. And patient cells with high CHK1 abundance were resistant to cytarabine.
However, when the researchers exposed the cells with high CHK1 abundance to the CHK1 inhibitor SCH900776, they observed “reduced clonogenic ability and progression of DNA replication in the presence of cytarabine.”
The team therefore concluded that treatment with a CHK1 inhibitor might overcome resistance to cytarabine-based treatments in AML. They also said that monitoring CHEK1 expression in AML patients could potentially predict outcomes and reveal patients who might benefit from treatment with a CHK1 inhibitor.
The second study was conducted by Isabel Morgado-Palacin, of the Spanish National Cancer Research Center in Madrid, and colleagues.
The researchers investigated ATR, which is the primary sensor of DNA replication stress, and ATM, a kinase that senses DNA double-strand breaks, as possible therapeutic targets in MLL-rearranged AML.
The team found that inhibiting ATR induced chromosomal breakage and death in murine AML-MLL cells in vitro. And inhibiting ATR in vivo reduced the tumor burden and prevented tumors from growing.
The researchers also found that inhibiting ATM prolonged survival in the mouse model of AML-MLL, which suggests that both ATR and ATM might be therapeutic targets in MLL-rearranged AML.
Image by NIGMS
A pair of studies suggest the DNA replication checkpoint pathway could be targeted to treat resistant acute myeloid leukemia (AML).
One study indicated that the kinase CHK1, which coordinates the DNA damage response and cell-cycle checkpoint response, might be targeted to overcome cytarabine resistance in AML.
The other study suggested that ATR, a kinase that activates CHK1, and ATM, a second upstream kinase in the DNA damage response, might be therapeutic targets in MLL-rearranged AML.
Both studies were published in Science Sigaling.
Laure David, of La Ligue Contre Le Cancer in Toulouse, France, and colleagues conducted this study.
The researchers integrated gene expression data with survival data from 198 AML patients who were previously treated with cytarabine-based chemotherapy.
The data showed that patients with high expression of CHEK1, the gene that encodes CHK1, had poor survival. And patient cells with high CHK1 abundance were resistant to cytarabine.
However, when the researchers exposed the cells with high CHK1 abundance to the CHK1 inhibitor SCH900776, they observed “reduced clonogenic ability and progression of DNA replication in the presence of cytarabine.”
The team therefore concluded that treatment with a CHK1 inhibitor might overcome resistance to cytarabine-based treatments in AML. They also said that monitoring CHEK1 expression in AML patients could potentially predict outcomes and reveal patients who might benefit from treatment with a CHK1 inhibitor.
The second study was conducted by Isabel Morgado-Palacin, of the Spanish National Cancer Research Center in Madrid, and colleagues.
The researchers investigated ATR, which is the primary sensor of DNA replication stress, and ATM, a kinase that senses DNA double-strand breaks, as possible therapeutic targets in MLL-rearranged AML.
The team found that inhibiting ATR induced chromosomal breakage and death in murine AML-MLL cells in vitro. And inhibiting ATR in vivo reduced the tumor burden and prevented tumors from growing.
The researchers also found that inhibiting ATM prolonged survival in the mouse model of AML-MLL, which suggests that both ATR and ATM might be therapeutic targets in MLL-rearranged AML.
Pregnancy screening lacking in girls with AML, ALL
patient and her father
Photo by Rhoda Baer
Many adolescent females are not being screened for pregnancy before beginning chemotherapy or undergoing computed tomography (CT) scans, according to research published in Cancer.
In this study, pregnancy screening was underused in adolescents with acute lymphoblastic leukemia (ALL), those with acute myeloid leukemia (AML), and those who received CT scans of the abdomen or pelvis during visits to the emergency room (ER).
“We found that adolescent girls are not adequately screened for pregnancy prior to receiving chemotherapy or CT scans that could harm a developing fetus,” said study author Pooja Rao, MD, of Penn State Health’s Milton S. Hershey Medical Center in Hershey, Pennsylvania.
“Adolescents with ALL, the most common childhood cancer, had the lowest rates of pregnancy screening of the patients we studied.”
Dr Rao and her colleagues examined pregnancy screening patterns among adolescent females newly diagnosed with ALL or AML, as well as adolescent females who visited the ER and received CT scans of the abdomen or pelvis. (In emergency medicine, pregnancy screening protocols exist for adolescents prior to receiving radiation due to the known teratogenic risks of radiation.)
The analysis included patients ages 10 to 18 who were admitted to hospitals across the US from 1999 to 2011. There were a total of 35,650 patient visits—127 for AML patients, 889 for ALL patients, and 34,634 ER admissions with CT scans of the abdomen/pelvis.
The proportion of visits with an appropriately timed pregnancy test was 35% for the ALL patients, 64% for the AML patients, and 58% in the ER group.
The researchers noted that ALL patients tended to be younger than the AML patients and the ER patients, and there was substantial variation in pregnancy screening patterns among the different hospitals.
However, in a generalized estimating equation (GEE) model adjusted for hospital clustering and patient age, patients with ALL were significantly less likely to have an appropriately timed pregnancy test when compared to patients in the ER cohort. The adjusted prevalence ratio was 0.71 (95% CI, 0.65-0.78).
And in a GEE model adjusted for hospital clustering, patients with AML were more likely to have an appropriately timed pregnancy test than patients in the ER cohort, but this difference was not statistically significant. The adjusted prevalence ratio was 1.12 (95% CI, 0.99-1.27).
The researchers also found that pregnancy screening continued to increase over time in the ALL cohort but remained “relatively stable” from 2008 onward in the AML and ER cohorts.
“Since nearly all chemotherapy agents used for childhood/adolescent acute leukemia can cause potential harm to a developing fetus, our findings indicate a need for standardized pregnancy screening practices for adolescent patients being treated for cancer,” Dr Rao said.
She also noted that the low rates of pregnancy screening observed in this study may indicate a reluctance on the part of pediatric oncologists to discuss sexual health practices with adolescent patients.
“While sexual health discussions and education may traditionally be thought to be the responsibility of the patient’s primary care provider, adolescents with cancer will often see their oncologist frequently over the course of their cancer treatment and afterwards,” Dr Rao said. “Oncologists therefore are well-positioned to initiate discussions about sexual health with their patients.”
patient and her father
Photo by Rhoda Baer
Many adolescent females are not being screened for pregnancy before beginning chemotherapy or undergoing computed tomography (CT) scans, according to research published in Cancer.
In this study, pregnancy screening was underused in adolescents with acute lymphoblastic leukemia (ALL), those with acute myeloid leukemia (AML), and those who received CT scans of the abdomen or pelvis during visits to the emergency room (ER).
“We found that adolescent girls are not adequately screened for pregnancy prior to receiving chemotherapy or CT scans that could harm a developing fetus,” said study author Pooja Rao, MD, of Penn State Health’s Milton S. Hershey Medical Center in Hershey, Pennsylvania.
“Adolescents with ALL, the most common childhood cancer, had the lowest rates of pregnancy screening of the patients we studied.”
Dr Rao and her colleagues examined pregnancy screening patterns among adolescent females newly diagnosed with ALL or AML, as well as adolescent females who visited the ER and received CT scans of the abdomen or pelvis. (In emergency medicine, pregnancy screening protocols exist for adolescents prior to receiving radiation due to the known teratogenic risks of radiation.)
The analysis included patients ages 10 to 18 who were admitted to hospitals across the US from 1999 to 2011. There were a total of 35,650 patient visits—127 for AML patients, 889 for ALL patients, and 34,634 ER admissions with CT scans of the abdomen/pelvis.
The proportion of visits with an appropriately timed pregnancy test was 35% for the ALL patients, 64% for the AML patients, and 58% in the ER group.
The researchers noted that ALL patients tended to be younger than the AML patients and the ER patients, and there was substantial variation in pregnancy screening patterns among the different hospitals.
However, in a generalized estimating equation (GEE) model adjusted for hospital clustering and patient age, patients with ALL were significantly less likely to have an appropriately timed pregnancy test when compared to patients in the ER cohort. The adjusted prevalence ratio was 0.71 (95% CI, 0.65-0.78).
And in a GEE model adjusted for hospital clustering, patients with AML were more likely to have an appropriately timed pregnancy test than patients in the ER cohort, but this difference was not statistically significant. The adjusted prevalence ratio was 1.12 (95% CI, 0.99-1.27).
The researchers also found that pregnancy screening continued to increase over time in the ALL cohort but remained “relatively stable” from 2008 onward in the AML and ER cohorts.
“Since nearly all chemotherapy agents used for childhood/adolescent acute leukemia can cause potential harm to a developing fetus, our findings indicate a need for standardized pregnancy screening practices for adolescent patients being treated for cancer,” Dr Rao said.
She also noted that the low rates of pregnancy screening observed in this study may indicate a reluctance on the part of pediatric oncologists to discuss sexual health practices with adolescent patients.
“While sexual health discussions and education may traditionally be thought to be the responsibility of the patient’s primary care provider, adolescents with cancer will often see their oncologist frequently over the course of their cancer treatment and afterwards,” Dr Rao said. “Oncologists therefore are well-positioned to initiate discussions about sexual health with their patients.”
patient and her father
Photo by Rhoda Baer
Many adolescent females are not being screened for pregnancy before beginning chemotherapy or undergoing computed tomography (CT) scans, according to research published in Cancer.
In this study, pregnancy screening was underused in adolescents with acute lymphoblastic leukemia (ALL), those with acute myeloid leukemia (AML), and those who received CT scans of the abdomen or pelvis during visits to the emergency room (ER).
“We found that adolescent girls are not adequately screened for pregnancy prior to receiving chemotherapy or CT scans that could harm a developing fetus,” said study author Pooja Rao, MD, of Penn State Health’s Milton S. Hershey Medical Center in Hershey, Pennsylvania.
“Adolescents with ALL, the most common childhood cancer, had the lowest rates of pregnancy screening of the patients we studied.”
Dr Rao and her colleagues examined pregnancy screening patterns among adolescent females newly diagnosed with ALL or AML, as well as adolescent females who visited the ER and received CT scans of the abdomen or pelvis. (In emergency medicine, pregnancy screening protocols exist for adolescents prior to receiving radiation due to the known teratogenic risks of radiation.)
The analysis included patients ages 10 to 18 who were admitted to hospitals across the US from 1999 to 2011. There were a total of 35,650 patient visits—127 for AML patients, 889 for ALL patients, and 34,634 ER admissions with CT scans of the abdomen/pelvis.
The proportion of visits with an appropriately timed pregnancy test was 35% for the ALL patients, 64% for the AML patients, and 58% in the ER group.
The researchers noted that ALL patients tended to be younger than the AML patients and the ER patients, and there was substantial variation in pregnancy screening patterns among the different hospitals.
However, in a generalized estimating equation (GEE) model adjusted for hospital clustering and patient age, patients with ALL were significantly less likely to have an appropriately timed pregnancy test when compared to patients in the ER cohort. The adjusted prevalence ratio was 0.71 (95% CI, 0.65-0.78).
And in a GEE model adjusted for hospital clustering, patients with AML were more likely to have an appropriately timed pregnancy test than patients in the ER cohort, but this difference was not statistically significant. The adjusted prevalence ratio was 1.12 (95% CI, 0.99-1.27).
The researchers also found that pregnancy screening continued to increase over time in the ALL cohort but remained “relatively stable” from 2008 onward in the AML and ER cohorts.
“Since nearly all chemotherapy agents used for childhood/adolescent acute leukemia can cause potential harm to a developing fetus, our findings indicate a need for standardized pregnancy screening practices for adolescent patients being treated for cancer,” Dr Rao said.
She also noted that the low rates of pregnancy screening observed in this study may indicate a reluctance on the part of pediatric oncologists to discuss sexual health practices with adolescent patients.
“While sexual health discussions and education may traditionally be thought to be the responsibility of the patient’s primary care provider, adolescents with cancer will often see their oncologist frequently over the course of their cancer treatment and afterwards,” Dr Rao said. “Oncologists therefore are well-positioned to initiate discussions about sexual health with their patients.”
10 recommendations for the Cancer Moonshot
Responding to the Cancer Moonshot initiative, a panel of scientists, clinicians, patient advocates, and industry representatives has issued 10 recommendations for accelerating cancer research in an article published in Science.
The recommendations address:
• Development of a patient engagement network.
• Precise cataloging of tumor molecular changes.
• Analysis of samples already available from patients who have received the standard of care.
• Improvements for data sharing, access, and analysis.
• Development of models to understand how childhood cancers develop.
• Research to describe how fusion oncoproteins drive cancer development.
• Creation of a cancer immunotherapy clinical trials network.
• Systematic efforts to gather information on patient-reported outcomes.
• Implementation of evidence-based approaches to prevention.
The panel’s recommendations were presented to the National Cancer Advisory Board, the adviser to the National Cancer Institute. The ability to conduct research stemming from the panel’s recommendations will depend on whether, and how much, funding is approved by Congress.
Read the article here: http://science.sciencemag.org/content/early/2016/09/07/science.aai7862.full.
Responding to the Cancer Moonshot initiative, a panel of scientists, clinicians, patient advocates, and industry representatives has issued 10 recommendations for accelerating cancer research in an article published in Science.
The recommendations address:
• Development of a patient engagement network.
• Precise cataloging of tumor molecular changes.
• Analysis of samples already available from patients who have received the standard of care.
• Improvements for data sharing, access, and analysis.
• Development of models to understand how childhood cancers develop.
• Research to describe how fusion oncoproteins drive cancer development.
• Creation of a cancer immunotherapy clinical trials network.
• Systematic efforts to gather information on patient-reported outcomes.
• Implementation of evidence-based approaches to prevention.
The panel’s recommendations were presented to the National Cancer Advisory Board, the adviser to the National Cancer Institute. The ability to conduct research stemming from the panel’s recommendations will depend on whether, and how much, funding is approved by Congress.
Read the article here: http://science.sciencemag.org/content/early/2016/09/07/science.aai7862.full.
Responding to the Cancer Moonshot initiative, a panel of scientists, clinicians, patient advocates, and industry representatives has issued 10 recommendations for accelerating cancer research in an article published in Science.
The recommendations address:
• Development of a patient engagement network.
• Precise cataloging of tumor molecular changes.
• Analysis of samples already available from patients who have received the standard of care.
• Improvements for data sharing, access, and analysis.
• Development of models to understand how childhood cancers develop.
• Research to describe how fusion oncoproteins drive cancer development.
• Creation of a cancer immunotherapy clinical trials network.
• Systematic efforts to gather information on patient-reported outcomes.
• Implementation of evidence-based approaches to prevention.
The panel’s recommendations were presented to the National Cancer Advisory Board, the adviser to the National Cancer Institute. The ability to conduct research stemming from the panel’s recommendations will depend on whether, and how much, funding is approved by Congress.
Read the article here: http://science.sciencemag.org/content/early/2016/09/07/science.aai7862.full.
How AML suppresses hematopoiesis
Exosomes shed by acute myeloid leukemia (AML) cells carry microRNAs that directly impair hematopoiesis, according to preclinical research published in Science Signaling.
Previous research suggested that AML exosomes can suppress residual hematopoietic stem and progenitor cell (HSPC) function indirectly through stromal reprogramming of niche retention factors.
The new study indicates that AML exosomes can block hematopoiesis by delivering microRNAs that directly suppress blood production when taken up by HSPCs.
Noah Hornick, of Oregon Health & Science University in Portland, and his colleagues conducted this study, isolating exosomes from cultures of human AML cells and from the plasma of mice with AML.
The researchers found these exosomes were enriched in 2 microRNAs—miR-150 and miR-155.
When cultured with HSPCs, the exosomes suppressed the expression of the transcription factor c-MYB, which is involved in HSPC proliferation and differentiation.
Blocking the function of miR-155 prevented AML cells or their exosomes from reducing c-MYB abundance and inhibiting the proliferation of cultured HSPCs.
Using a method called RISC-Trap, the researchers identified other targets of microRNAs in AML exosomes, from which they predicted protein networks that could be disrupted in cells taking up the exosomes.
The team said this study suggests that interfering with exosome-delivered microRNAs in the bone marrow or restoring the abundance of their targets may enhance AML patients’ ability to produce healthy blood cells.
Exosomes shed by acute myeloid leukemia (AML) cells carry microRNAs that directly impair hematopoiesis, according to preclinical research published in Science Signaling.
Previous research suggested that AML exosomes can suppress residual hematopoietic stem and progenitor cell (HSPC) function indirectly through stromal reprogramming of niche retention factors.
The new study indicates that AML exosomes can block hematopoiesis by delivering microRNAs that directly suppress blood production when taken up by HSPCs.
Noah Hornick, of Oregon Health & Science University in Portland, and his colleagues conducted this study, isolating exosomes from cultures of human AML cells and from the plasma of mice with AML.
The researchers found these exosomes were enriched in 2 microRNAs—miR-150 and miR-155.
When cultured with HSPCs, the exosomes suppressed the expression of the transcription factor c-MYB, which is involved in HSPC proliferation and differentiation.
Blocking the function of miR-155 prevented AML cells or their exosomes from reducing c-MYB abundance and inhibiting the proliferation of cultured HSPCs.
Using a method called RISC-Trap, the researchers identified other targets of microRNAs in AML exosomes, from which they predicted protein networks that could be disrupted in cells taking up the exosomes.
The team said this study suggests that interfering with exosome-delivered microRNAs in the bone marrow or restoring the abundance of their targets may enhance AML patients’ ability to produce healthy blood cells.
Exosomes shed by acute myeloid leukemia (AML) cells carry microRNAs that directly impair hematopoiesis, according to preclinical research published in Science Signaling.
Previous research suggested that AML exosomes can suppress residual hematopoietic stem and progenitor cell (HSPC) function indirectly through stromal reprogramming of niche retention factors.
The new study indicates that AML exosomes can block hematopoiesis by delivering microRNAs that directly suppress blood production when taken up by HSPCs.
Noah Hornick, of Oregon Health & Science University in Portland, and his colleagues conducted this study, isolating exosomes from cultures of human AML cells and from the plasma of mice with AML.
The researchers found these exosomes were enriched in 2 microRNAs—miR-150 and miR-155.
When cultured with HSPCs, the exosomes suppressed the expression of the transcription factor c-MYB, which is involved in HSPC proliferation and differentiation.
Blocking the function of miR-155 prevented AML cells or their exosomes from reducing c-MYB abundance and inhibiting the proliferation of cultured HSPCs.
Using a method called RISC-Trap, the researchers identified other targets of microRNAs in AML exosomes, from which they predicted protein networks that could be disrupted in cells taking up the exosomes.
The team said this study suggests that interfering with exosome-delivered microRNAs in the bone marrow or restoring the abundance of their targets may enhance AML patients’ ability to produce healthy blood cells.
Extramedullary disease did not independently predict AML survival
Extramedullary disease is common in newly diagnosed acute myeloid leukemia, and frequently occurs in at least two sites, but is not an independent prognostic factor for overall survival, according to an analysis of 11 clinical trials.
“Importantly, the presence of extramedullary disease should not affect the choice of post-remission therapy,” concluded Dr. Chezi Ganzel of Shaare Zedek Medical Center, Jerusalem, Israel, together with his associates on behalf of the ECOG-ACRIN Cancer Research Group.
Extramedullary disease was found in anywhere from 2% to 30% of AML patients in past studies, and its prognostic impact was “unfavorable in some reports, but not in others,” the investigators noted. To help clarify the issue, they studied patients aged 15 years and up with newly diagnosed AML from 11 clinical trials conducted between 1980 and 2008. The initial study population included 3,522 patients, of which 282 were excluded for having promyelocytic leukemia (168 patients), leukemia that was not AML (29 patieints), no baseline assessment of extramedullary disease (41 patients), no survival data (20 patients), or no eligibility for retrospective central review (24 patients). That left 3,240 patients, of whom 769 (24%) had extramedullary disease. The most commonly involved sites included the lymph nodes (about 12% of patients), spleen (7%), liver (5%), skin (5%), and gingiva (4%). Only 1% of patients had detectable central nervous system involvement. Most (65%) of patients had one site of extramedullary disease, while 21% had two sites, and the rest had more extensive involvement (J Clin Oncol. 2016 Aug 29. doi: 10.1200/JCO.2016.67.1305).
Rates of complete remission were 59.7% overall, 59% among patients with extramedullary disease, and 60% among patients without extramedullary disease, the investigators said. Just as the presence of extramedullary disease did not significantly affect the likelihood of complete remission, nor did any specific site of extramedullary disease, although there was a non-significant trend toward lower rates of complete remission among patients with splenic or gingival involvement.
The median overall survival for the cohort was 1 year. Univariate analyses linked the presence of any extramedullary disease (P = .005) and involvement of the skin (P = .002), spleen (P less than .001), and liver (P less than .001) with shorter overall survival. However, none of these relationships held up in a multivariable analysis that accounted for other significant prognostic factors, including earlier year of registration, older age, high white blood cell count, low platelet count, poor performance status, high cytogenetic risk status, and not achieving a complete remission, said the researchers.“It is possible that individual sites of extramedullary disease are, in fact, associated with poorer prognosis [but that] these patients also have other unfavorable prognostic factors, such as high white blood cell count and unfavorable cytogenetics,” the researchers commented.
Based on this large study, treatment decisions “should be made on the basis of recognized AML prognostic factors, irrespective of the presence of extramedullary disease,” they concluded.
The National Institutes of Health supported the work. Dr. Ganzel had no disclosures.
Extramedullary disease is common in newly diagnosed acute myeloid leukemia, and frequently occurs in at least two sites, but is not an independent prognostic factor for overall survival, according to an analysis of 11 clinical trials.
“Importantly, the presence of extramedullary disease should not affect the choice of post-remission therapy,” concluded Dr. Chezi Ganzel of Shaare Zedek Medical Center, Jerusalem, Israel, together with his associates on behalf of the ECOG-ACRIN Cancer Research Group.
Extramedullary disease was found in anywhere from 2% to 30% of AML patients in past studies, and its prognostic impact was “unfavorable in some reports, but not in others,” the investigators noted. To help clarify the issue, they studied patients aged 15 years and up with newly diagnosed AML from 11 clinical trials conducted between 1980 and 2008. The initial study population included 3,522 patients, of which 282 were excluded for having promyelocytic leukemia (168 patients), leukemia that was not AML (29 patieints), no baseline assessment of extramedullary disease (41 patients), no survival data (20 patients), or no eligibility for retrospective central review (24 patients). That left 3,240 patients, of whom 769 (24%) had extramedullary disease. The most commonly involved sites included the lymph nodes (about 12% of patients), spleen (7%), liver (5%), skin (5%), and gingiva (4%). Only 1% of patients had detectable central nervous system involvement. Most (65%) of patients had one site of extramedullary disease, while 21% had two sites, and the rest had more extensive involvement (J Clin Oncol. 2016 Aug 29. doi: 10.1200/JCO.2016.67.1305).
Rates of complete remission were 59.7% overall, 59% among patients with extramedullary disease, and 60% among patients without extramedullary disease, the investigators said. Just as the presence of extramedullary disease did not significantly affect the likelihood of complete remission, nor did any specific site of extramedullary disease, although there was a non-significant trend toward lower rates of complete remission among patients with splenic or gingival involvement.
The median overall survival for the cohort was 1 year. Univariate analyses linked the presence of any extramedullary disease (P = .005) and involvement of the skin (P = .002), spleen (P less than .001), and liver (P less than .001) with shorter overall survival. However, none of these relationships held up in a multivariable analysis that accounted for other significant prognostic factors, including earlier year of registration, older age, high white blood cell count, low platelet count, poor performance status, high cytogenetic risk status, and not achieving a complete remission, said the researchers.“It is possible that individual sites of extramedullary disease are, in fact, associated with poorer prognosis [but that] these patients also have other unfavorable prognostic factors, such as high white blood cell count and unfavorable cytogenetics,” the researchers commented.
Based on this large study, treatment decisions “should be made on the basis of recognized AML prognostic factors, irrespective of the presence of extramedullary disease,” they concluded.
The National Institutes of Health supported the work. Dr. Ganzel had no disclosures.
Extramedullary disease is common in newly diagnosed acute myeloid leukemia, and frequently occurs in at least two sites, but is not an independent prognostic factor for overall survival, according to an analysis of 11 clinical trials.
“Importantly, the presence of extramedullary disease should not affect the choice of post-remission therapy,” concluded Dr. Chezi Ganzel of Shaare Zedek Medical Center, Jerusalem, Israel, together with his associates on behalf of the ECOG-ACRIN Cancer Research Group.
Extramedullary disease was found in anywhere from 2% to 30% of AML patients in past studies, and its prognostic impact was “unfavorable in some reports, but not in others,” the investigators noted. To help clarify the issue, they studied patients aged 15 years and up with newly diagnosed AML from 11 clinical trials conducted between 1980 and 2008. The initial study population included 3,522 patients, of which 282 were excluded for having promyelocytic leukemia (168 patients), leukemia that was not AML (29 patieints), no baseline assessment of extramedullary disease (41 patients), no survival data (20 patients), or no eligibility for retrospective central review (24 patients). That left 3,240 patients, of whom 769 (24%) had extramedullary disease. The most commonly involved sites included the lymph nodes (about 12% of patients), spleen (7%), liver (5%), skin (5%), and gingiva (4%). Only 1% of patients had detectable central nervous system involvement. Most (65%) of patients had one site of extramedullary disease, while 21% had two sites, and the rest had more extensive involvement (J Clin Oncol. 2016 Aug 29. doi: 10.1200/JCO.2016.67.1305).
Rates of complete remission were 59.7% overall, 59% among patients with extramedullary disease, and 60% among patients without extramedullary disease, the investigators said. Just as the presence of extramedullary disease did not significantly affect the likelihood of complete remission, nor did any specific site of extramedullary disease, although there was a non-significant trend toward lower rates of complete remission among patients with splenic or gingival involvement.
The median overall survival for the cohort was 1 year. Univariate analyses linked the presence of any extramedullary disease (P = .005) and involvement of the skin (P = .002), spleen (P less than .001), and liver (P less than .001) with shorter overall survival. However, none of these relationships held up in a multivariable analysis that accounted for other significant prognostic factors, including earlier year of registration, older age, high white blood cell count, low platelet count, poor performance status, high cytogenetic risk status, and not achieving a complete remission, said the researchers.“It is possible that individual sites of extramedullary disease are, in fact, associated with poorer prognosis [but that] these patients also have other unfavorable prognostic factors, such as high white blood cell count and unfavorable cytogenetics,” the researchers commented.
Based on this large study, treatment decisions “should be made on the basis of recognized AML prognostic factors, irrespective of the presence of extramedullary disease,” they concluded.
The National Institutes of Health supported the work. Dr. Ganzel had no disclosures.
FROM THE JOURNAL OF CLINICAL ONCOLOGY
Key clinical point: Extramedullary disease does not appear to independently predict overall survival in patients with newly diagnosed acute myeloid leukemia.
Major finding: Neither extramedullary disease in general nor any specific site independently predicted overall survival in the multivariable analysis.
Data source: An analysis of 3,240 patients aged 15 years and older with newly diagnosed AML who were part of 11 clinical trials.
Disclosures: The National Institutes of Health supported the work. Dr. Ganzel had no disclosures.