Gene Mutations and Maturity Linked to Drug Resistance in Acute Leukemia
Acute myeloid leukemia is a rapidly progressing blood and bone marrow cancer predominantly affecting older adults.
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An international team led by the University of Colorado Cancer Center has identified key factors influencing the effectiveness of a common treatment for acute myeloid leukemia (AML). Their analysis, published today in Blood Cancer Discovery, examined data from 678 patients, the largest cohort to date for this therapy, revealing how specific gene mutations and the developmental stage of leukemia cells shape treatment response.
Understanding treatment variability in AML
AML is a rapidly progressing blood and bone marrow cancer predominantly affecting older adults. Many patients cannot undergo intensive chemotherapy, so they receive a combination of venetoclax and hypomethylating agents (HMA), which has extended survival for some. However, responses vary widely, and resistance remains a significant hurdle.
The study highlights that patients with a subtype known as monocytic AML experience poorer outcomes, particularly if they lack the NPM1 gene mutation, which is generally associated with better prognosis. These patients also frequently carry other mutations, such as KRAS, that correlate with resistance to venetoclax plus HMA.
In addition to genetic factors, the maturity of leukemia cells at treatment initiation was found to influence survival outcomes. This dual consideration of gene mutations and cell maturity offers a more comprehensive understanding of why some patients fail to respond to therapy.
Implications for personalized treatment approaches
By uncovering how AML cells evade venetoclax-based treatment, the findings provide a foundation for developing therapies that block these resistance pathways. The research also supports refined risk stratification, enabling clinicians to better identify which patients are likely to benefit from this drug combination and which may require alternative strategies.
The researchers plan to expand their dataset and design clinical trials incorporating this classification model to guide treatment decisions more precisely.
Key scientific terms
Acute myeloid leukemia (AML)
A fast-growing cancer of the blood and bone marrow characterized by the rapid proliferation of abnormal white blood cells.Venetoclax
A targeted drug that inhibits the protein BCL-2, helping to induce cancer cell death in certain blood cancers.Hypomethylating agents (HMA)
Drugs that modify DNA methylation patterns, which can reactivate suppressed genes and improve the effectiveness of cancer treatment.Gene mutations
Changes in the DNA sequence of a gene that can affect how cells grow and respond to therapies.Monocytic AML
A subtype of AML where the leukemic cells resemble monocytes, a type of white blood cell.Reference: Curtis A. Lachowiez CA, Heiblig M, Aspas Requena, et al. Genetic and Phenotypic correlates of clinical outcomes with Venetoclax in Acute Myeloid Leukemia: The GEN-PHEN-VEN study. Blood Cancer Discovery. 2025. doi:10.1158/2643-3230.BCD-24-0256
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