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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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A Gain-Of-Function P53-Mutant Oncogene Promotes Cell Fate Plasticity and Myeloid Leukemia Through the Pluripotency Factor FOXH1 Published OnlineFirst May 8, 2019; DOI: 10.1158/2159-8290.CD-18-1391 RESEARCH ARTICLE A Gain-of-Function p53-Mutant Oncogene Promotes Cell Fate Plasticity and Myeloid Leukemia through the Pluripotency Factor FOXH1 Evangelia Loizou1,2, Ana Banito1, Geulah Livshits1, Yu-Jui Ho1, Richard P. Koche3, Francisco J. Sánchez-Rivera1, Allison Mayle1, Chi-Chao Chen1, Savvas Kinalis4, Frederik O. Bagger4,5, Edward R. Kastenhuber1,6, Benjamin H. Durham7, and Scott W. Lowe1,8 Downloaded from cancerdiscovery.aacrjournals.org on September 27, 2021. © 2019 American Association for Cancer Research. Published OnlineFirst May 8, 2019; DOI: 10.1158/2159-8290.CD-18-1391 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 Trp53 R172H muta- tion (TP53 R175H in humans) exhibits a neomorphic function by promoting aberrant self-renewal in leu- kemic 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 fi de 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 transcrip- tion 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. INTRODUCTION capacity to transactivate wild-type target genes, despite being frequently stabilized owing to reduced interaction with neg- TP53 mutations occur in the majority of human cancers and ative regulators ( 10 ). These mutant proteins can instill neo- are often associated with poor outcomes ( 1, 2 ). TP53 encodes morphic gain-of-function (GOF) activities that contribute to a sequence-specifi c transcription factor (3) that is normally cancer phenotypes beyond p53 loss ( 11 ). At the organismal maintained at low levels through strict post-translational con- level, mice harboring certain germline missense mutations trol ( 4 ). In response to DNA damage, activated oncogenes, or in Trp53 develop an altered tumor spectrum compared with other forms of cellular stress, p53 is stabilized and promotes Trp53 -null mice, including a larger fraction of epithelial can- cell-cycle arrest, apoptosis, senescence, or other antiprolifera- cers with increased metastatic potential ( 12, 13 ). At the cellu- tive programs depending on cellular context ( 5–8 ). Most TP53 lar level, some GOF p53 mutants promote chemoresistance, mutations occur in the DNA binding domain and disrupt invasiveness, and/or an epithelial-to-mesenchymal transi- its transcriptional activity, thereby preventing these stress tion (EMT) through diverse mechanisms ( 12–14 ). Another responses and enabling aberrant proliferation and survival of neomorphic function of mutant p53 involves its ability to mutated cells ( 9 ). facilitate the formation of induced pluripotent stem cells Cancer-associated mutations typically inactivate p53 (iPSC) more so than p53 loss ( 15, 16 ), although the extent through a two-hit mechanism, whereby one allele acquires to which this GOF activity is relevant to cancer is poorly a missense mutation and the other undergoes “loss-of- understood. heterozygosity” (LOH) via chromosomal deletion ( 8 ). Mis- In contrast to their high prevalence in most solid tumors, sense TP53 mutations encode proteins that have attenuated TP53 mutations occur in around 10% of blood cancers, although when they occur they are associated with poor prognosis ( 17, 18 ). In acute myeloid leukemia (AML), TP53 1 Cancer Biology and Genetics Program, Sloan Kettering Institute, Memo- mutations are associated with a subtype known as complex rial Sloan Kettering Cancer Center, New York, New York. 2 Weill Cornell karyotype AML (CK-AML), which is defi ned by the presence Graduate School of Medical Sciences, New York, New York. 3 Center for of three or more cytogenetic abnormalities and a dismal Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, New York. 4 Center for Genomic Medicine, Rigshopitalet, University of 5-year survival rate of less than 2% ( 17, 18 ). Functional stud- Copenhagen, Copenhagen, Denmark. 5 Department of Biomedicine and ies in mice indicate that Trp53 inactivation in the hematopoi- Swiss Institute of Bioinformatics, UKBB Universitats-Kinderspital, Basel, etic compartment can produce chemoresistant malignancies Switzerland. 6 Louis V. Gerstner Jr. Graduate School of Biomedical Sci- with increased leukemia-initiating potential, mirroring key ences, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, features linked to TP53 mutations in patients with AML New York, New York. 7 Human Oncology and Pathogenesis Program, Memo- rial Sloan Kettering Cancer Center, New York, New York. 8 Howard Hughes (19–21 ). Still, whether and how TP53 missense mutations Medical Institute, New York, New York. confer GOF activities to p53 in AML is not known. Note: Supplementary data for this article are available at Cancer Discovery In this study, we set out to test whether mutant p53 has Online (http://cancerdiscovery.aacrjournals.org/). GOF activity in AML and, if so, to determine the underlying Corresponding Author: Scott W. Lowe, Memorial Sloan Kettering Cancer mechanisms behind this effect. We chose to study Trp53 R172H Center, 417 E 68 th Street, Box 373, New York, NY 10065. Phone: 646- (R175H in humans), a mutant form of Trp53 that has been 888-3342; Fax: 646-888-3347; E-mail: [email protected] shown to confer GOF activity in solid tumors and is the Cancer Discov 2019;9:962–79 most common allele in patients with AML (Dr. Elli Papaem- doi: 10.1158/2159-8290.CD-18-1391 manuil, personal communication). Several complementary © 2019 American Association for Cancer Research. in vitro and in vivo systems were used to compare the biological JULY 2019 CANCER DISCOVERY | 963 Downloaded from cancerdiscovery.aacrjournals.org on September 27, 2021. © 2019 American Association for Cancer Research. Published OnlineFirst May 8, 2019; DOI: 10.1158/2159-8290.CD-18-1391 RESEARCH ARTICLE Loizou et al. features of wild-type, Trp53-null, or Trp53-mutant alleles, functional evidence that a Trp53-mutant allele can contribute leading us to identify a neomorphic function of mutant to AML beyond the effects of p53 loss. p53 in hematopoietic stem and progenitor cells (HSPC) that exerts its effect by enhancing cellular self-renewal beyond that Sustained Expression of Mutant p53 Is Required R172H produced by p53 inactivation. We also identify a novel medi- for the Maintenance of p53 Leukemic Cells ator of mutant p53 function, FOXH1, which contributes to We next examined whether the p53R172H-mutant protein the aberrant self-renewal phenotype. As such, suppression of was required for survival of p53-mutant leukemic cells. We either mutant p53 or FOXH1 ablates this stemness capacity utilized previously characterized Trp53Δ/Δ or Trp53R172H/Δ and by triggering differentiation. These observations illustrate Trp53R172H/11B3 CK-AML murine cell lines that were created how mutant p53 can acquire a pro-oncogenic activity that by cotransduction of short hairpin RNAs (shRNA) target- magnifies loss of its tumor-suppressive functions and creates ing Nf1 (GFP-labeled) and Mll3 (mCherry-labeled), hereafter a previously unappreciated molecular dependency in AML. referred to as PNM (20, 26). These cell lines were generated to reflect the most common genetic configurations found in Δ/Δ R172H RESULTS patients, including Trp53 loss alone (Trp53 ), Trp53 over a focal Trp53 deletion (Trp53R172H/Δ), or Trp53R172H over a larger R172H p53 Accelerates the Onset of Hematologic genomic deletion that encompasses Trp53 (Trp53R172H/11B3; ref. Malignancies beyond Effects of p53 Deficiency 25). Control shRNAs against Renilla luciferase (sh.Ren) or We first compared the ability of a mutant or nullTrp53 allele Trp53 (sh.p53) were coexpressed with a blue fluorescent protein to promote leukemogenesis in a well-defined genetic model. (BFP) reporter (Supplementary Fig. S1A; ref. 27). The percent- Because of its previously defined GOF activity in other set- age of BFP+ cells was monitored over time as a measurement of tings, we used a conditional mutant Trp53 allele harboring fitness under the two shRNA-containing conditions. an R172H mutation downstream of a “lox-stop-lox” cassette We observed a significant reduction in the relative number (LSL-Trp53R172H; ref. 12), which corresponds to TP53R175H, the of sh.p53 BFP+ cells compared with sh.Ren BFP+ cells over time most frequent missense mutation in clinical cases of AML (18). (Fig. 2A, light blue and dark blue lines), indicating negative Mouse cohorts were produced to harbor one Trp53R172H allele selection against cells in which the mutant protein is depleted. and a Trp53 floxed allele (Trp53LSL-R172H/F), or were homozygous In contrast, sh.p53 had no effect on Trp53Δ/Δ AML cells, rul- for the floxedTrp53 allele (Trp53F/F), such that all hematopoietic ing out potential off-target effects
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