Precision and strategic targeting of novel mutation-specific vulnerabilities in acute myeloid leukemia: the semi-centennial of 7 + 3

Abstract

The year 2023 marks the semi-centennial of the introduction of classic ‘7 + 3’ chemotherapy for acute myeloid leukemia (AML) in 1973. It also marks the decennial of the first comprehensive sequencing efforts from The Cancer Genome Atlas (TCGA), which revealed that dozens of unique genes are recurrently mutated in AML genomes. Although more than 30 distinct genes have been implicated in AML pathogenesis, the current therapeutic armamentarium that is commercially available only targets FLT3 and IDH1/2 mutations, with olutasidenib as the most recent addition. This focused review spotlights management approaches that exploit the exquisite molecular dependencies of specific subsets of AML, with an emphasis on emerging therapies in the pipeline, including agents targeting TP53-mutant cells. We summarize precision and strategic targeting of AML based on leveraging functional dependencies and explore how mechanisms involving critical gene products can inform rational therapeutic design in 2024.

Keywords:

• Acute myeloid leukemia
• targeted therapies
• mutational testing
• TP53
• metabolic vulnerabilities

Ethical approval

There was no testing or experimentation involving animals, patients, or other subjects.

Disclosure statement

SAP serves on the Acute Myeloid Leukemia advisory board for Bristol Myers Squibb and served on the Multiple Myeloma advisory board for Pfizer.

Data availability statement

There was no new data generated.

Additional information

Funding

SAP receives research funding from the UMass Center for Clinical and Translational Science (CCTS) Pilot Project Program grant [NIH/NCATS Grant UL1TR001453].