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and Matt McCormack, PhD
Photo courtesy of the
Walter and Eliza Hall
Institute of Medical Research
Preclinical research suggests the Hhex protein could be a cancer-specific therapeutic target for acute myeloid leukemia (AML).
Investigators discovered that loss of the Hhex protein halted leukemia cell growth and division in vitro and in vivo, but normal cells were unaffected by the loss of Hhex.
Matt McCormack, PhD, of the Walter and Eliza Hall Institute of Medical Research in Parkville, Victoria, Australia, and his colleagues relayed these findings in Genes and Development.
“There is an urgent need for new therapies to treat AML,” Dr McCormack said. “We showed blocking the Hhex protein could put the brakes on leukemia growth and completely eliminate AML in preclinical models. This could be targeted by new drugs to treat AML in humans.”
Specifically, the investigators found that Hhex was overexpressed in human AML, and the protein was essential for the maintenance of AML driven by the oncogenic fusion protein MLL-ENL and its downstream effectors, HoxA9 and Meis1.
However, Hhex was not required for normal myelopoiesis.
“Hhex is only essential for the leukemic cells, meaning we could target and treat leukemia without toxic effects on normal cells, avoiding many of the serious side effects that come with standard cancer treatments,” Dr McCormack said.
“We also know that most people with AML have increased levels of Hhex, often associated with adverse outcomes, further indicating it is an important target for new AML drugs.”
Dr McCormack and his colleagues also attempted to determine the mechanism by which Hhex promotes AML.
They found the protein represses the tumor suppressors p16INK4a and p19ARF in leukemic stem cells by regulating the Polycomb-repressive complex 2 (PRC2). They said that Hhex binds to the Cdkn2a locus and directly interacts with PRC2 to enable H3K27me3-mediated epigenetic repression.
“Hhex works by recruiting epigenetic factors to growth-control genes, effectively silencing them,” said author Ben Shields, PhD, also of the Walter and Eliza Hall Institute.
“This allows the leukemia cells to reproduce and accumulate more damage, contributing to the speed of AML progression.”
Dr McCormack said that although drugs inhibiting epigenetic modification have been tested against AML in the past, they have caused significant toxicity because their targets are also required for normal blood cell function.
“Unlike the epigenetic factors targeted previously, Hhex only regulates a small number of genes and is dispensable for normal blood cells,” Dr McCormack reiterated.
“This gives us a rare opportunity to kill AML cells without causing many side effects. We now hope to identify the critical regions of the Hhex protein that enable it to function, which will allow us to design much-needed new drugs to treat AML.” 
and Matt McCormack, PhD
Photo courtesy of the
Walter and Eliza Hall
Institute of Medical Research
Preclinical research suggests the Hhex protein could be a cancer-specific therapeutic target for acute myeloid leukemia (AML).
Investigators discovered that loss of the Hhex protein halted leukemia cell growth and division in vitro and in vivo, but normal cells were unaffected by the loss of Hhex.
Matt McCormack, PhD, of the Walter and Eliza Hall Institute of Medical Research in Parkville, Victoria, Australia, and his colleagues relayed these findings in Genes and Development.
“There is an urgent need for new therapies to treat AML,” Dr McCormack said. “We showed blocking the Hhex protein could put the brakes on leukemia growth and completely eliminate AML in preclinical models. This could be targeted by new drugs to treat AML in humans.”
Specifically, the investigators found that Hhex was overexpressed in human AML, and the protein was essential for the maintenance of AML driven by the oncogenic fusion protein MLL-ENL and its downstream effectors, HoxA9 and Meis1.
However, Hhex was not required for normal myelopoiesis.
“Hhex is only essential for the leukemic cells, meaning we could target and treat leukemia without toxic effects on normal cells, avoiding many of the serious side effects that come with standard cancer treatments,” Dr McCormack said.
“We also know that most people with AML have increased levels of Hhex, often associated with adverse outcomes, further indicating it is an important target for new AML drugs.”
Dr McCormack and his colleagues also attempted to determine the mechanism by which Hhex promotes AML.
They found the protein represses the tumor suppressors p16INK4a and p19ARF in leukemic stem cells by regulating the Polycomb-repressive complex 2 (PRC2). They said that Hhex binds to the Cdkn2a locus and directly interacts with PRC2 to enable H3K27me3-mediated epigenetic repression.
“Hhex works by recruiting epigenetic factors to growth-control genes, effectively silencing them,” said author Ben Shields, PhD, also of the Walter and Eliza Hall Institute.
“This allows the leukemia cells to reproduce and accumulate more damage, contributing to the speed of AML progression.”
Dr McCormack said that although drugs inhibiting epigenetic modification have been tested against AML in the past, they have caused significant toxicity because their targets are also required for normal blood cell function.
“Unlike the epigenetic factors targeted previously, Hhex only regulates a small number of genes and is dispensable for normal blood cells,” Dr McCormack reiterated.
“This gives us a rare opportunity to kill AML cells without causing many side effects. We now hope to identify the critical regions of the Hhex protein that enable it to function, which will allow us to design much-needed new drugs to treat AML.”
and Matt McCormack, PhD
Photo courtesy of the
Walter and Eliza Hall
Institute of Medical Research
Preclinical research suggests the Hhex protein could be a cancer-specific therapeutic target for acute myeloid leukemia (AML).
Investigators discovered that loss of the Hhex protein halted leukemia cell growth and division in vitro and in vivo, but normal cells were unaffected by the loss of Hhex.
Matt McCormack, PhD, of the Walter and Eliza Hall Institute of Medical Research in Parkville, Victoria, Australia, and his colleagues relayed these findings in Genes and Development.
“There is an urgent need for new therapies to treat AML,” Dr McCormack said. “We showed blocking the Hhex protein could put the brakes on leukemia growth and completely eliminate AML in preclinical models. This could be targeted by new drugs to treat AML in humans.”
Specifically, the investigators found that Hhex was overexpressed in human AML, and the protein was essential for the maintenance of AML driven by the oncogenic fusion protein MLL-ENL and its downstream effectors, HoxA9 and Meis1.
However, Hhex was not required for normal myelopoiesis.
“Hhex is only essential for the leukemic cells, meaning we could target and treat leukemia without toxic effects on normal cells, avoiding many of the serious side effects that come with standard cancer treatments,” Dr McCormack said.
“We also know that most people with AML have increased levels of Hhex, often associated with adverse outcomes, further indicating it is an important target for new AML drugs.”
Dr McCormack and his colleagues also attempted to determine the mechanism by which Hhex promotes AML.
They found the protein represses the tumor suppressors p16INK4a and p19ARF in leukemic stem cells by regulating the Polycomb-repressive complex 2 (PRC2). They said that Hhex binds to the Cdkn2a locus and directly interacts with PRC2 to enable H3K27me3-mediated epigenetic repression.
“Hhex works by recruiting epigenetic factors to growth-control genes, effectively silencing them,” said author Ben Shields, PhD, also of the Walter and Eliza Hall Institute.
“This allows the leukemia cells to reproduce and accumulate more damage, contributing to the speed of AML progression.”
Dr McCormack said that although drugs inhibiting epigenetic modification have been tested against AML in the past, they have caused significant toxicity because their targets are also required for normal blood cell function.
“Unlike the epigenetic factors targeted previously, Hhex only regulates a small number of genes and is dispensable for normal blood cells,” Dr McCormack reiterated.
“This gives us a rare opportunity to kill AML cells without causing many side effects. We now hope to identify the critical regions of the Hhex protein that enable it to function, which will allow us to design much-needed new drugs to treat AML.”