AML | Icahn School of Medicine

Identifying Acute Myeloid Leukemia Gene Mutations

A study published in the journal Nature from the laboratory of Eirini Papapetrou, MD, PhD, provides new insights into acute myeloid leukemia (AML) and its resistance to a common treatment.

AML is a devastating blood cancer that starts in the bone marrow, where blood stem cells are born. Although it is a rare disease, approximately 22,000 people were diagnosed with AML in 2025 in the United States, with roughly 11,000 deaths, according to the American Cancer Society. In this study, researchers found that certain genetic changes, known as RAS mutations, can make leukemia stem cells resistant to drugs. The RAS gene family includes KRAS, HRAS, and NRAS, which encode proteins that control cell signaling, growth, and death. Mutations in these genes typically appear later in the disease and specifically target certain blood cell types, making them more aggressive and harder to treat.

“We discovered that these RAS-mutant leukemia stem cells behave differently from other leukemia stem cells,” said Dr. Papapetrou. “This could explain why some patients do not respond well to the widely used drug venetoclax, which the Food and Drug Administration approved for AML treatment in October 2020.”

The study used innovative genetically engineered models and patient-derived cells, combined with advanced genomic technologies, to investigate the role of RAS mutations in leukemia and their impact on drug response. The researchers discovered that RAS mutations specifically target granulocyte-monocyte progenitors that have already acquired early mutations, transforming them into RAS-mutant leukemia stem cells. This leads to leukemias with distinct characteristics, including resistance to venetoclax. This resistance is caused by changes in proteins that control apoptosis, a form of cell death, impacted by RAS mutations.

“This study has implications for patients with RAS mutations,” Dr. Papapetrou said. “It suggests that treatment with venetoclax might not be effective for these individuals and could even worsen their condition. For these patients, providers should consider a combination of therapies that include new RAS inhibitors, which could improve treatment results.”

“Our study supports the rationale of testing combinations of venetoclax with RAS inhibitors, as well as MCL-1 and/or BCL-xL inhibitors,” Dr. Papapetrou continued. “Such inhibitors are currently at different stages of preclinical and clinical development and, based on our results, could be tested in combination with venetoclax in patients with AML with RAS mutations.”

The findings highlight the importance of personalized medicine, where treatments are tailored to the specific genetic characteristics of each patient's cancer. This approach could lead to better outcomes and improved quality of life for those battling leukemia. The study involved collaboration with several leading medical institutions and received support from the National Institutes of Health and various philanthropic foundations.