Journal
CANCER DISCOVERY
Volume 9, Issue 7, Pages 962-979Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-18-1391
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Funding
- NCI [R01 CA190261]
- Memorial Sloan Kettering Cancer Center Support Grant [P30 CA008748]
- Dorris J. Hutchison Student Fellowship (SKD)
- European Molecular Biology Organization
- F31 National Research Service Award predoctoral fellowship from the NCI/NIH [F31CA192835]
- MSKCC Translational Research Oncology Training Fellowship (NIH) [T32-CA160001]
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Mutations in the TP53 tumor suppressor gene are common in many cancer types, including the acute myeloid leukemia (AML) subtype known as complex karyotype AML (CK-AML). Here, we identify a gain-of-function (GOF) Trp53 mutation that accelerates CK-AML initiation beyond p53 loss and, surprisingly, is required for disease maintenance. The Trp53(R172H) mutation (TP53(R175H) in humans) exhibits a neomorphic function by promoting aberrant self-renewal in leukemic cells, a phenotype that is present in hematopoietic stem and progenitor cells (HSPC) even prior to their transformation. We identify FOXH1 as a critical mediator of mutant p53 function that binds to and regulates stem cell-associated genes and transcriptional programs. Our results identify a context where mutant p53 acts as a bona fide oncogene that contributes to the pathogenesis of CK-AML and suggests a common biological theme for TP53 GOF in cancer. SIGNIFICANCE: Our study demonstrates how a GOF p53 mutant can hijack an embryonic transcription factor to promote aberrant self-renewal. In this context, mutant Trp53 functions as an oncogene to both initiate and sustain myeloid leukemia and suggests a potential convergent activity of mutant Trp53 across cancer types.
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