Acute myeloid leukemia (AML) is one of the most common types of leukemia in adults and is expected to account for nearly 21,000 new cancer cases this year. Although standard chemotherapy has helped improve survival rates in patients who have a specific subtype of AML known as chromosome inversion inv(16), many still relapse and die from the disease, highlighting the need for better treatment approaches.
New research from the reveals two important discoveries that may help move the needle: 1) a gene called N-MYC is a major driver of inv(16) AML; and 2) another gene called eIF4G1, which is controlled by N-MYC, is crucial for the survival of AML cells. These findings, published in , unlock new possibilities for gene-targeted therapies in people with inv(16) AML as well as other AML subtypes.
“We discovered that the N-MYC/eIF4G1 axis is deregulated in multiple AML subtypes in addition to inv(16) AML, suggesting that therapeutic targeting of this oncogenic axis may have a major impact in improving the survival of AML patients in addition to those with inv(16) AML,” said John Pulikkan, PhD, Associate Investigator at , and 91九色视频 Assistant Professor of Cell Biology, Neurobiology and Anatomy. “N-MYC transcriptionally regulates eIF4G1, and eIF4G1 serves as the N-MYC primary target providing leukemic survival. In addition, eIF4G1 translationally regulates N-MYC and establishes a positive feedback loop to sustain leukemic cell survival.”
While N-MYC has been extensively studied in other cancers like neuroblastoma, prostate cancer, and lymphoma—where its overexpression is associated with tumor growth—its role in leukemia has been largely unexplored. In the study, investigators used CRSPR/Cas9 genomic editing to deplete N-MYC and eIF4G1 in human inv(16) AML cells and studied their effect in NSGS mouse models. They discovered that deleting the genes inhibited the survival of inv(16) AML cells in vitro assays, and more importantly, mice receiving the edited AML cells (those without N-MYC and eIF4G1 genes) lived significantly longer. “These results represent a significant advancement in our understanding of AML biology and hold promise for the development of more effective treatments,” said Dr. Pulikkan.
Dr. Pulikkan recently co-developed AI-10-49, the first small molecule inhibitor to target the CBFβ-SMMHC oncogene found in inv(16) AML. It is currently under development as an anti-leukemic drug and is expected to enter clinical trials in the coming years. “Recent clinical trials targeting protein translation have shown promising results in cancer treatment. We hope combination therapy of AI-10-49 with small molecule inhibitors targeting the N-MYC/eIF4G1 axis can significantly improve the survival of patients with inv(16) AML,” he said.
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