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

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Bibliographische Detailangaben
Zeitschriftentitel:	Cancer Discovery
Personen und Körperschaften:	Loizou, Evangelia, Banito, Ana, Livshits, Geulah, Ho, Yu-Jui, Koche, Richard P., Sánchez-Rivera, Francisco J., Mayle, Allison, Chen, Chi-Chao, Kinalis, Savvas, Bagger, Frederik O., Kastenhuber, Edward R., Durham, Benjamin H., Lowe, Scott W.
In:	Cancer Discovery, 9, 2019, 7, S. 962-979
Format:	E-Article
Sprache:	Englisch
veröffentlicht:	American Association for Cancer Research (AACR)
Schlagwörter:	Oncology

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Zusammenfassung:	<jats:title>Abstract</jats:title> <jats:sec> <jats:title /> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Significance:</jats:title> <jats:p>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.</jats:p> <jats:p>This article is highlighted in the In This Issue feature, p. 813</jats:p> </jats:sec>
Umfang:	962-979
ISSN:	2159-8274 2159-8290
DOI:	10.1158/2159-8290.cd-18-1391