Combating MYCN-Driven Leukemogenesis May Benefit AML Patients

It may be possible to block MYCN-driven leukemogenesis and combat acute myeloid leukemia (AML) in an entirely new way. Researchers at St. Jude Children’s Research Hospital report in JCI Insight that they have discovered a vulnerability that may easily translate into new targeted drug therapies that block heme biosynthesis, killing leukemic cells.

Pediatric leukemia patients have elevated excretion of porphyrins, intermediates of the heme biosynthetic pathway. Using an extensive genomic database, the team searched for genes that were abnormally switched on in a virulent form of AML that is driven by the oncogene MYCN. They found that one gene in particular, UROD, was highly activated in this type of AML. UROD is part of the molecular machinery that synthesizes heme. The team investigated if MYCN overexpression in murine hematopoietic progenitor cells affected UROD expression.

Study investigator John D. Schuetz, PhD, of the department of pharmaceutical sciences at St. Jude Children’s Research Hospital in Memphis, said that it appears that MYCN-driven leukemias with the most overactivated UROD are much more lethal. In the laboratory, the researchers found that cells with overactivated MYCN consumed more oxygen and depended on the production of heme to propagate and become cancerous. However, suppressing heme production prevented self-renewal.

“Instead of inhibiting the production of heme, we took advantage of this aberrant metabolic change by ramping up the accumulation of its toxic precursors, porphyrins. The addition of a nontoxic earlier precursor γ-aminolevulinate (ALA) combined with inhibition of the export of porphyrins eliminated leukemia in a mouse AML model,” Schuetz told OncoTherapy Network.

The researchers screened bioactive compounds approved by the US Food and Drug Administration for their ability to inhibit the export of toxic porphyrins. They identified some potent and promising inhibitors that kill AML cells when combined with ALA in vitro.

Based on these new findings, the researchers theorize that the upregulation of heme biosynthesis may be providing a key advantage to MYCN hematopoietic progenitors, facilitating oncogenic transformation. Schuetz said that these findings suggest two new drug strategies to treat AML. One strategy could target UROD, which would reduce heme biosynthesis. The other strategy would involve developing drugs to inhibit a relief-valve protein and simultaneously administer an agent that is a precursor of heme.

Schuetz noted that other cancers with an overactivated heme pathway such as medulloblastoma might also be vulnerable to such a treatment strategy.

“We will be launching preclinical studies using a mouse AML model to test the combination therapy shortly. If it proves successful, we would make recommendations to move forward with a clinical study,” said Schuetz