A Gain-of-Function p53-Mutant Oncogene Promotes Cell Fate Plasticity and Myeloid Leukemia through the Pluripotency Factor FOXH1

Abstract

Mutations in the <i>TP53</i> 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) <i>Trp53</i> mutation that accelerates CK-AML initiation beyond p53 loss and, surprisingly, is required for disease maintenance. The <i>Trp53^R172H</i> mutation (<i>TP53^R175H</i> 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 <i>TP53</i> 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 <i>Trp53</i> functions as an oncogene to both initiate and sustain myeloid leukemia and suggests a potential convergent activity of mutant <i>Trp53</i> across cancer types.<i>This article is highlighted in the In This Issue feature, p. 813</i>.