A gain-of-function p53-mutant oncogene promotes cell fate plasticity and myeloid leukemia through the pluripotency factor FOXH1 Journal Article
| Authors: | Loizou, E.; Banito, A.; Livshits, G.; Ho, Y. J.; Koche, R. P.; Sánchez-Rivera, F. J.; Mayle, A.; Chen, C. C.; Kinalis, S.; Bagger, F. O.; Kastenhuber, E. R.; Durham, B. H.; Lowe, S. W. |
| Article Title: | A gain-of-function p53-mutant oncogene promotes cell fate plasticity and myeloid leukemia through the pluripotency factor FOXH1 |
| Abstract: | 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 Trp53R172H mutation (TP53R175H 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.This article is highlighted in the In This Issue feature, p. 813. ©2019 American Association for Cancer Research. |
| Journal Title: | Cancer Discovery |
| Volume: | 9 |
| Issue: | 7 |
| ISSN: | 2159-8274 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2019-07-01 |
| Start Page: | 962 |
| End Page: | 979 |
| Language: | English |
| DOI: | 10.1158/2159-8290.Cd-18-1391 |
| PUBMED: | 31068365 |
| PROVIDER: | scopus |
| PMCID: | PMC6606372 |
| DOI/URL: | |
| Notes: | Source: Scopus |
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