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Researchers have found evidence to suggest that a type of acute myeloid leukemia (AML) depends on the production of heme.
The group’s work has revealed 2 ways to target heme synthesis that might be used to treat this type of AML, which is driven by the oncogene MYCN.
John Schuetz, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleague described this research in JCI Insight.
Previous research had suggested that heme production was affected in leukemia.
However, Dr Schuetz said, “Absolutely nothing was known about the role of heme biosynthesis [in AML] before our work.”
The researchers’ first clue regarding heme’s role in AML arose from a computer search. The team searched a genomic database for other genes that were abnormally switched on in MYCN-driven AML.
They found that UROD was highly activated and noted that UROD is part of the molecular machinery that synthesizes heme.
Especially significant, Dr Schuetz said, was the finding that MYCN-driven AML with the most over-activated UROD was far more lethal than other AMLs.
The researchers found that cells with over-activated MYCN consumed more oxygen and depended on the production of heme for self-renewal and oncogenic transformation. But the team was able to block cancer cell self-renewal in the MYCN cells by blocking heme synthesis.
The researchers also found they could suppress self-renewal by blocking ABCG2, a “relief-valve” molecule that rids the cells of porphyrin, a building-block molecule of heme.
Blocking ABCG2 caused the buildup of porphyrin, which is toxic to the leukemia cells. However, blocking ABCG2 in normal cells produced no ill effects.
In mouse models of MYCN leukemia, the researchers tested a strategy of knocking out ABCG2. These knockout mice had significantly slower disease progression and longer survival.
What’s more, the team found they could cure leukemia in these mice by inhibiting ABCG2 and ramping up the heme machinery.
“Our findings suggest 2 drug strategies to treat AML,” Dr Schuetz said. “One would be to target UROD, which would reduce heme biosynthesis. Such drugs would selectively affect leukemia cells because they are so dependent on heme.”
“The other strategy would be to use drugs to inhibit the relief-valve protein and, at the same time, administer a chemical that is a precursor of heme. This would cause a buildup of toxic molecules that are part of the heme synthesis pathway.”
Dr Schuetz said other cancers with an over-activated heme pathway might also be vulnerable to such a treatment strategy.
He and his colleagues plan to extend their understanding of the heme machinery in AML with further studies. For example, they don’t know whether heme’s role in cell respiration is the only important one in supporting AML progression, since heme plays a wide range of roles in cells.
The researchers are also planning to test whether drugs that suppress UROD function in the heme-production machinery can effectively battle AML. 
Researchers have found evidence to suggest that a type of acute myeloid leukemia (AML) depends on the production of heme.
The group’s work has revealed 2 ways to target heme synthesis that might be used to treat this type of AML, which is driven by the oncogene MYCN.
John Schuetz, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleague described this research in JCI Insight.
Previous research had suggested that heme production was affected in leukemia.
However, Dr Schuetz said, “Absolutely nothing was known about the role of heme biosynthesis [in AML] before our work.”
The researchers’ first clue regarding heme’s role in AML arose from a computer search. The team searched a genomic database for other genes that were abnormally switched on in MYCN-driven AML.
They found that UROD was highly activated and noted that UROD is part of the molecular machinery that synthesizes heme.
Especially significant, Dr Schuetz said, was the finding that MYCN-driven AML with the most over-activated UROD was far more lethal than other AMLs.
The researchers found that cells with over-activated MYCN consumed more oxygen and depended on the production of heme for self-renewal and oncogenic transformation. But the team was able to block cancer cell self-renewal in the MYCN cells by blocking heme synthesis.
The researchers also found they could suppress self-renewal by blocking ABCG2, a “relief-valve” molecule that rids the cells of porphyrin, a building-block molecule of heme.
Blocking ABCG2 caused the buildup of porphyrin, which is toxic to the leukemia cells. However, blocking ABCG2 in normal cells produced no ill effects.
In mouse models of MYCN leukemia, the researchers tested a strategy of knocking out ABCG2. These knockout mice had significantly slower disease progression and longer survival.
What’s more, the team found they could cure leukemia in these mice by inhibiting ABCG2 and ramping up the heme machinery.
“Our findings suggest 2 drug strategies to treat AML,” Dr Schuetz said. “One would be to target UROD, which would reduce heme biosynthesis. Such drugs would selectively affect leukemia cells because they are so dependent on heme.”
“The other strategy would be to use drugs to inhibit the relief-valve protein and, at the same time, administer a chemical that is a precursor of heme. This would cause a buildup of toxic molecules that are part of the heme synthesis pathway.”
Dr Schuetz said other cancers with an over-activated heme pathway might also be vulnerable to such a treatment strategy.
He and his colleagues plan to extend their understanding of the heme machinery in AML with further studies. For example, they don’t know whether heme’s role in cell respiration is the only important one in supporting AML progression, since heme plays a wide range of roles in cells.
The researchers are also planning to test whether drugs that suppress UROD function in the heme-production machinery can effectively battle AML.
Researchers have found evidence to suggest that a type of acute myeloid leukemia (AML) depends on the production of heme.
The group’s work has revealed 2 ways to target heme synthesis that might be used to treat this type of AML, which is driven by the oncogene MYCN.
John Schuetz, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleague described this research in JCI Insight.
Previous research had suggested that heme production was affected in leukemia.
However, Dr Schuetz said, “Absolutely nothing was known about the role of heme biosynthesis [in AML] before our work.”
The researchers’ first clue regarding heme’s role in AML arose from a computer search. The team searched a genomic database for other genes that were abnormally switched on in MYCN-driven AML.
They found that UROD was highly activated and noted that UROD is part of the molecular machinery that synthesizes heme.
Especially significant, Dr Schuetz said, was the finding that MYCN-driven AML with the most over-activated UROD was far more lethal than other AMLs.
The researchers found that cells with over-activated MYCN consumed more oxygen and depended on the production of heme for self-renewal and oncogenic transformation. But the team was able to block cancer cell self-renewal in the MYCN cells by blocking heme synthesis.
The researchers also found they could suppress self-renewal by blocking ABCG2, a “relief-valve” molecule that rids the cells of porphyrin, a building-block molecule of heme.
Blocking ABCG2 caused the buildup of porphyrin, which is toxic to the leukemia cells. However, blocking ABCG2 in normal cells produced no ill effects.
In mouse models of MYCN leukemia, the researchers tested a strategy of knocking out ABCG2. These knockout mice had significantly slower disease progression and longer survival.
What’s more, the team found they could cure leukemia in these mice by inhibiting ABCG2 and ramping up the heme machinery.
“Our findings suggest 2 drug strategies to treat AML,” Dr Schuetz said. “One would be to target UROD, which would reduce heme biosynthesis. Such drugs would selectively affect leukemia cells because they are so dependent on heme.”
“The other strategy would be to use drugs to inhibit the relief-valve protein and, at the same time, administer a chemical that is a precursor of heme. This would cause a buildup of toxic molecules that are part of the heme synthesis pathway.”
Dr Schuetz said other cancers with an over-activated heme pathway might also be vulnerable to such a treatment strategy.
He and his colleagues plan to extend their understanding of the heme machinery in AML with further studies. For example, they don’t know whether heme’s role in cell respiration is the only important one in supporting AML progression, since heme plays a wide range of roles in cells.
The researchers are also planning to test whether drugs that suppress UROD function in the heme-production machinery can effectively battle AML.