Are there new genetic risks identified for Acute Myeloid Leukemia in specific gene locations?

Researchers have found several new genetic locations linked to a higher risk of developing acute myeloid leukemia (AML). A large meta-analysis of genome-wide association studies (GWAS) identified four new risk loci, including one at chromosome 2p23.3 that also affects survival. In addition, known mutations in genes like FLT3, NPM1, and TP53 remain important for diagnosis and treatment. These discoveries help doctors better understand who might be at risk and how to personalize therapy.

What the research says

A 2024 meta-analysis of 4,710 AML cases and 12,938 controls found a new genome-wide significant risk locus for all types of AML at chromosome 2p23.3 (rs4665765), which also linked to patient survival ⁵. The same study identified three new risk loci for specific AML subgroups: 1q23.3 (DUSP23) for AML with deletions of chromosomes 5 and/or 7, and 2q33.3 (PARD3B) and 2p21 (EPCAM) for cytogenetically complex AML ⁵. These findings expand the known heritable risk factors beyond familial syndromes.

Other genetic markers are also critical. FLT3 mutations, especially internal tandem duplications (ITD), are common in AML and guide treatment with targeted drugs like quizartinib and gilteritinib ¹⁷. NPM1 mutations are the most frequent genetic lesion in adult AML and define a distinct disease subtype ¹⁰. TP53 mutations, particularly multihit changes, are linked to very poor outcomes, with only 7% two-year survival in one study ². Mutations in IDH1, SRSF2, and DDX41 also affect prognosis and treatment response ²⁴.

Some genetic changes are tied to specific therapies. For example, CPX-351 improves survival in AML with myelodysplasia-related changes (AML-MR) but not in TP53-mutated AML ²⁴. The EVI1 gene, often with MLL rearrangements, is a high-risk marker that may respond to combinations like ATRA and VAH ⁸. These genetic insights are increasingly used to personalize treatment and predict outcomes.

What to ask your doctor

• Should I have genetic testing for the newly identified risk loci (e.g., 2p23.3, 1q23.3) if I have a family history of AML?
• Do my AML cells have FLT3, NPM1, or TP53 mutations, and how do they affect my treatment options?
• Is my AML subtype classified as AML with myelodysplasia-related changes, and would CPX-351 be a good choice for me?
• What is my genetic risk group according to the European LeukemiaNet classification, and what does that mean for my prognosis?
• Are there any clinical trials testing new targeted therapies based on my specific genetic mutations?