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

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  2. Single mRNP Analysis Reveals that Small Cytoplasmic mRNP Granules Represent mRNA Singletons

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  3. Deconvolution of autoencoders to learn biological regulatory modules from single cell mRNA sequencing data

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  4. Deep targeted sequencing of TP53 in chronic lymphocytic leukemia: clinical impact at diagnosis and at time of treatment

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  5. The splicing factor RBM25 controls MYC activity in acute myeloid leukemia

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  • Evangelia Loizou
  • Ana Banito
  • Geulah Livshits
  • Yu-Jui Ho
  • Richard P Koche
  • Francisco J Sánchez-Rivera
  • Allison Mayle
  • Chi-Chao Chen
  • Savvas Kinalis
  • Frederik O Bagger
  • Edward R Kastenhuber
  • Benjamin H Durham
  • Scott W Lowe
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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 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.

Original languageEnglish
JournalCancer Discovery
Volume9
Issue number7
Pages (from-to)962-979
Number of pages18
ISSN2159-8274
DOIs
Publication statusPublished - Jul 2019

ID: 58986328