{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,12]],"date-time":"2026-11-12T12:39:32Z","timestamp":1794487172661,"version":"4.9.1"},"reference-count":71,"publisher":"Springer Science and Business Media LLC","issue":"11","license":[{"start":{"date-parts":[[2023,9,14]],"date-time":"2023-09-14T00:00:00Z","timestamp":1694649600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2023,9,14]],"date-time":"2023-09-14T00:00:00Z","timestamp":1694649600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Leukemia"],"published-print":{"date-parts":[[2023,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Hematopoietic stem cells (HSCs) ensure blood cell production during the life-time of an organism, and to do so they need to balance self-renewal, proliferation, differentiation, and migration in a steady state as well as in response to stress or injury. Importantly, aberrant proliferation of HSCs leads to hematological malignancies, and thus, tight regulation by various tumor suppressor pathways, including p53, is essential. Protein phosphatase magnesium-dependent 1 delta (PPM1D) is a negative regulator of p53 and promotes cell survival upon induction of genotoxic stress. Truncating mutations in the last exon of <jats:italic>PPM1D<\/jats:italic> lead to the production of a stable, enzymatically active protein and are commonly associated with clonal hematopoiesis. Using a transgenic mouse model, we demonstrate that truncated PPM1D reduces self-renewal of HSCs in basal conditions but promotes the development of aggressive AML after exposure to ionizing radiation. Inhibition of PPM1D suppressed the colony growth of leukemic stem and progenitor cells carrying the truncated PPM1D, and remarkably, it provided protection against irradiation-induced cell growth. Altogether, we demonstrate that truncated PPM1D affects HSC maintenance, disrupts normal hematopoiesis, and that its inhibition could be beneficial in the context of therapy-induced AML.<\/jats:p>","DOI":"10.1038\/s41375-023-02030-8","type":"journal-article","created":{"date-parts":[[2023,9,14]],"date-time":"2023-09-14T14:41:02Z","timestamp":1694702462000},"page":"2209-2220","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Ppm1d truncating mutations promote the development of genotoxic stress-induced AML"],"prefix":"10.1038","volume":"37","author":[{"given":"Monika","family":"Burocziova","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petr","family":"Danek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2483-3739","authenticated-orcid":false,"given":"Anna","family":"Oravetzova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zuzana","family":"Chalupova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8093-641X","authenticated-orcid":false,"given":"Meritxell","family":"Alberich-Jorda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0987-1238","authenticated-orcid":false,"given":"Libor","family":"Macurek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,9,14]]},"reference":[{"key":"2030_CR1","doi-asserted-by":"publisher","first-page":"5118","DOI":"10.1182\/blood-2012-05-356014","volume":"120","author":"V Pant","year":"2012","unstructured":"Pant V, Quint\u00e1s-Cardama A, Lozano G. The p53 pathway in hematopoiesis: lessons from mouse models, implications for humans. Blood. 2012;120:5118\u201327.","journal-title":"Blood"},{"key":"2030_CR2","doi-asserted-by":"publisher","first-page":"997","DOI":"10.1038\/nature02989","volume":"431","author":"K Ito","year":"2004","unstructured":"Ito K, Hirao A, Arai F, Matsuoka S, Takubo K, Hamaguchi I, et al. Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells. Nature. 2004;431:997\u20131002.","journal-title":"Nature."},{"key":"2030_CR3","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1038\/nature05159","volume":"443","author":"V Janzen","year":"2006","unstructured":"Janzen V, Forkert R, Fleming HE, Saito Y, Waring MT, Dombkowski DM, et al. Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a. Nature. 2006;443:421\u20136.","journal-title":"Nature"},{"key":"2030_CR4","doi-asserted-by":"publisher","first-page":"1001","DOI":"10.1016\/j.cell.2012.01.040","volume":"148","author":"J Wang","year":"2012","unstructured":"Wang J, Sun Q, Morita Y, Jiang H, Gross A, Lechel A, et al. A differentiation checkpoint limits hematopoietic stem cell self-renewal in response to DNA damage. Cell. 2012;148:1001\u201314.","journal-title":"Cell."},{"key":"2030_CR5","doi-asserted-by":"publisher","first-page":"1736","DOI":"10.1182\/blood-2006-03-010413","volume":"109","author":"M Dumble","year":"2007","unstructured":"Dumble M, Moore L, Chambers SM, Geiger H, Van Zant G, Goodell MA, et al. The impact of altered p53 dosage on hematopoietic stem cell dynamics during aging. Blood. 2007;109:1736\u201342.","journal-title":"Blood."},{"key":"2030_CR6","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1016\/j.stem.2008.11.006","volume":"4","author":"Y Liu","year":"2009","unstructured":"Liu Y, Elf SE, Miyata Y, Sashida G, Liu Y, Huang G, et al. p53 regulates hematopoietic stem cell quiescence. Cell Stem Cell. 2009;4:37\u201348.","journal-title":"Cell Stem Cell"},{"key":"2030_CR7","doi-asserted-by":"publisher","first-page":"1804","DOI":"10.1126\/science.287.5459.1804","volume":"287","author":"T Cheng","year":"2000","unstructured":"Cheng T, Rodrigues N, Shen H, Yang Y, Dombkowski D, Sykes M, et al. Hematopoietic stem cell quiescence maintained by p21cip1\/waf1. Science. 2000;287:1804\u20138.","journal-title":"Science"},{"key":"2030_CR8","doi-asserted-by":"publisher","first-page":"1389","DOI":"10.1101\/gad.1940710","volume":"24","author":"Z Zhao","year":"2010","unstructured":"Zhao Z, Zuber J, Diaz-Flores E, Lintault L, Kogan SC, Shannon K, et al. p53 loss promotes acute myeloid leukemia by enabling aberrant self-renewal. Genes Dev. 2010;24:1389\u2013402.","journal-title":"Genes Dev"},{"key":"2030_CR9","doi-asserted-by":"publisher","first-page":"6048","DOI":"10.1073\/pnas.94.12.6048","volume":"94","author":"M Fiscella","year":"1997","unstructured":"Fiscella M, Zhang H, Fan S, Sakaguchi K, Shen S, Mercer W. Wip1, a novel human protein phosphatase that is induced in response to ionizing radiation in a p53-dependent manner. Proc Natl Acad Sci USA. 1997;94:6048\u201353.","journal-title":"Proc Natl Acad Sci USA"},{"key":"2030_CR10","doi-asserted-by":"publisher","first-page":"180","DOI":"10.1016\/j.stem.2007.05.020","volume":"1","author":"ON Demidov","year":"2007","unstructured":"Demidov ON, Timofeev O, Lwin HNY, Kek C, Appella E, Bulavin DV. Wip1 phosphatase regulates p53-dependent apoptosis of stem cells and tumorigenesis in the mouse intestine. Cell Stem Cell. 2007;1:180\u201390.","journal-title":"Cell Stem Cell"},{"key":"2030_CR11","doi-asserted-by":"publisher","first-page":"1433","DOI":"10.1002\/stem.65","volume":"27","author":"YH Zhu","year":"2009","unstructured":"Zhu YH, Zhang CW, Lu L, Demidov ON, Sun L, Yang L, et al. Wip1 regulates the generation of new neural cells in the adult olfactory bulb through p53-dependent cell cycle control. Stem Cells. 2009;27:1433\u201342.","journal-title":"Stem Cells"},{"key":"2030_CR12","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms7808","volume":"6","author":"Z Chen","year":"2015","unstructured":"Chen Z, Yi W, Morita Y, Wang H, Cong Y, Liu J-P, et al. Wip1 deficiency impairs haematopoietic stem cell function via p53 and mTORC1 pathways. Nat Commun. 2015;6:6808.","journal-title":"Nat Commun"},{"key":"2030_CR13","doi-asserted-by":"publisher","first-page":"1162","DOI":"10.1101\/gad.1291305","volume":"19","author":"X Lu","year":"2005","unstructured":"Lu X, Nannenga B, Donehower L. PPM1D dephosphorylates Chk1 and p53 and abrogates cell cycle checkpoints. Genes Dev. 2005;19:1162\u201374.","journal-title":"Genes Dev"},{"key":"2030_CR14","doi-asserted-by":"publisher","first-page":"3196","DOI":"10.1038\/emboj.2009.246","volume":"28","author":"A Lindqvist","year":"2009","unstructured":"Lindqvist A, de Bruijn M, Macurek L, Bras A, Mensinga A, Bruinsma W. Wip1 confers G2 checkpoint recovery competence by counteracting p53-dependent transcriptional repression. EMBO J. 2009;28:3196\u2013206.","journal-title":"EMBO J"},{"key":"2030_CR15","doi-asserted-by":"publisher","first-page":"1963","DOI":"10.1002\/stem.121","volume":"27","author":"J-S Lee","year":"2009","unstructured":"Lee J-S, Lee M-O, Moon B-H, Shim SH, Fornace AJ, Cha H-J. Senescent growth arrest in mesenchymal stem cells is bypassed by Wip1-mediated downregulation of intrinsic stress signaling pathways. Stem Cells. 2009;27:1963\u201375.","journal-title":"Stem Cells"},{"key":"2030_CR16","doi-asserted-by":"publisher","first-page":"342","DOI":"10.1016\/j.ccr.2007.08.033","volume":"12","author":"X Lu","year":"2007","unstructured":"Lu X, Ma O, Nguyen T-A, Jones SN, Oren M, Donehower LA. The Wip1 phosphatase acts as a gatekeeper in the p53-Mdm2 autoregulatory loop. Cancer Cell. 2007;12:342\u201354.","journal-title":"Cancer Cell"},{"key":"2030_CR17","doi-asserted-by":"publisher","first-page":"9","DOI":"10.3390\/cells9092068","volume":"9","author":"AS Martinikova","year":"2020","unstructured":"Martinikova AS, Burocziova M, Stoyanov M, Macurek L. Truncated PPM1D prevents apoptosis in the murine thymus and promotes ionizing radiation-induced lymphoma. Cells. 2020;9:9.","journal-title":"Cells."},{"key":"2030_CR18","doi-asserted-by":"publisher","first-page":"2502","DOI":"10.1038\/sj.onc.1210032","volume":"26","author":"ON Demidov","year":"2006","unstructured":"Demidov ON, Kek C, Shreeram S, Timofeev O, Fornace AJ, Appella E, et al. The role of the MKK6\/\/p38 MAPK pathway in Wip1-dependent regulation of ErbB2-driven mammary gland tumorigenesis. Oncogene. 2006;26:2502\u20136.","journal-title":"Oncogene"},{"key":"2030_CR19","doi-asserted-by":"publisher","first-page":"4818","DOI":"10.4049\/jimmunol.176.8.4818","volume":"176","author":"M Schito","year":"2006","unstructured":"Schito M, Demidov O, Saito S, Ashwell J, Appella E. Wip1 phosphatase-deficient mice exhibit defective T cell maturation due to sustained p53 activation. J Immunol. 2006;176:4818\u201325.","journal-title":"J Immunol"},{"key":"2030_CR20","doi-asserted-by":"publisher","first-page":"3210","DOI":"10.4049\/jimmunol.1300363","volume":"191","author":"L Sun","year":"2013","unstructured":"Sun L, Li H, Luo H, Zhang L, Hu X, Yang T, et al. Phosphatase Wip1 is essential for the maturation and homeostasis of medullary thymic epithelial cells in mice. J Immunol. 2013;191:3210\u201320.","journal-title":"J Immunol"},{"key":"2030_CR21","doi-asserted-by":"publisher","first-page":"519","DOI":"10.1182\/blood-2012-05-432674","volume":"121","author":"G Liu","year":"2013","unstructured":"Liu G, Hu X, Sun B, Yang T, Shi J, Zhang L, et al. Phosphatase Wip1 negatively regulates neutrophil development through p38 MAPK-STAT1. Blood. 2013;121:519\u201329.","journal-title":"Blood"},{"key":"2030_CR22","doi-asserted-by":"publisher","first-page":"343","DOI":"10.1038\/ng1317","volume":"36","author":"DV Bulavin","year":"2004","unstructured":"Bulavin DV, Phillips C, Nannenga B, Timofeev O, Donehower LA, Anderson CW, et al. Inactivation of the Wip1 phosphatase inhibits mammary tumorigenesis through p38 MAPK-mediated activation of the p16Ink4a-p19Arf pathway. Nat Genet. 2004;36:343\u201350.","journal-title":"Nat Genet"},{"key":"2030_CR23","doi-asserted-by":"publisher","first-page":"2793","DOI":"10.1084\/jem.20061563","volume":"203","author":"S Shreeram","year":"2006","unstructured":"Shreeram S, Hee W, Demidov O, Kek C, Yamaguchi H, Fornace A. Regulation of ATM\/p53-dependent suppression of myc-induced lymphomas by Wip1 phosphatase. J Exp Med. 2006;203:2793\u20139.","journal-title":"J Exp Med"},{"key":"2030_CR24","doi-asserted-by":"publisher","first-page":"210","DOI":"10.1038\/ng894","volume":"31","author":"DV Bulavin","year":"2002","unstructured":"Bulavin DV, Demidov ON, Saito SI, Kauraniemi P, Phillips C, Amundson SA, et al. Amplification of PPM1D in human tumors abrogates p53 tumor-suppressor activity. Nat Genet. 2002;31:210.","journal-title":"Nat Genet"},{"key":"2030_CR25","doi-asserted-by":"crossref","unstructured":"Zhang L, Hsu JI, Goodell MA. PPM1D in Solid and Hematologic Malignancies: friend and foe? Mol Cancer Res. 2022;20:1365\u201378.","DOI":"10.1158\/1541-7786.MCR-21-1018"},{"key":"2030_CR26","doi-asserted-by":"publisher","first-page":"511","DOI":"10.1083\/jcb.201210031","volume":"201","author":"P Kleiblova","year":"2013","unstructured":"Kleiblova P, Shaltiel IA, Benada J, Sev\u010d\u00edk J, Pech\u00e1\u010dkov\u00e1 S, Pohlreich P, et al. Gain-of-function mutations of PPM1D\/Wip1 impair the p53-dependent G1 checkpoint. J Cell Biol. 2013;201:511\u201321.","journal-title":"J Cell Biol"},{"key":"2030_CR27","doi-asserted-by":"publisher","first-page":"818","DOI":"10.1038\/s41419-019-2057-4","volume":"10","author":"M Burocziova","year":"2019","unstructured":"Burocziova M, Burdova K, Martinikova AS, Kasparek P, Kleiblova P, Danielsen SA, et al. Truncated PPM1D impairs stem cell response to genotoxic stress and promotes growth of APC-deficient tumors in the mouse colon. Cell Death Dis. 2019;10:818.","journal-title":"Cell Death Dis"},{"key":"2030_CR28","doi-asserted-by":"publisher","first-page":"700","DOI":"10.1016\/j.stem.2018.10.004","volume":"23","author":"JI Hsu","year":"2018","unstructured":"Hsu JI, Dayaram T, Tovy A, De Braekeleer E, Jeong M, Wang F, et al. PPM1D mutations drive clonal hematopoiesis in response to cytotoxic chemotherapy. Cell Stem Cell. 2018;23:700\u201313.e6.","journal-title":"Cell Stem Cell"},{"key":"2030_CR29","doi-asserted-by":"publisher","first-page":"1095","DOI":"10.1182\/blood-2018-05-850339","volume":"132","author":"JD Kahn","year":"2018","unstructured":"Kahn JD, Miller PG, Silver AJ, Sellar RS, Bhatt S, Gibson C, et al. PPM1D truncating mutations confer resistance to chemotherapy and sensitivity to PPM1D inhibition in hematopoietic cells. Blood. 2018;132:1095.","journal-title":"Blood"},{"key":"2030_CR30","doi-asserted-by":"publisher","first-page":"1472","DOI":"10.1038\/nm.3733","volume":"20","author":"M Xie","year":"2014","unstructured":"Xie M, Lu C, Wang J, McLellan MD, Johnson KJ, Wendl MC, et al. Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nat Med. 2014;20:1472.","journal-title":"Nat Med"},{"key":"2030_CR31","doi-asserted-by":"publisher","first-page":"1155","DOI":"10.1038\/s41588-022-01121-z","volume":"54","author":"SP Kar","year":"2022","unstructured":"Kar SP, Quiros PM, Gu M, Jiang T, Mitchell J, Langdon R, et al. Genome-wide analyses of 200,453 individuals yield new insights into the causes and consequences of clonal hematopoiesis. Nat Genet. 2022;54:1155\u201366.","journal-title":"Nat Genet"},{"key":"2030_CR32","first-page":"1599","volume":"136","author":"JT Warren","year":"2020","unstructured":"Warren JT, Link DC. Clonal hematopoiesis and risk for hematologic malignancy. Blood. 2020;136:1599\u2013605.","journal-title":"Blood"},{"key":"2030_CR33","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-31878-0","volume":"13","author":"O Pich","year":"2022","unstructured":"Pich O, Reyes-Salazar I, Gonzalez-Perez A, Lopez-Bigas N. Discovering the drivers of clonal hematopoiesis. Nat Commun. 2022;13:4267.","journal-title":"Nat Commun"},{"key":"2030_CR34","doi-asserted-by":"publisher","first-page":"684","DOI":"10.1161\/CIRCRESAHA.121.319314","volume":"129","author":"Y Yura","year":"2021","unstructured":"Yura Y, Miura-Yura E, Katanasaka Y, Min KD, Chavkin N, Polizio AH, et al. The cancer therapy-related clonal hematopoiesis driver Gene Ppm1d promotes inflammation and non-ischemic heart failure in mice. Circ Res. 2021;129:684\u201398.","journal-title":"Circ Res"},{"key":"2030_CR35","doi-asserted-by":"publisher","first-page":"S107","DOI":"10.1016\/j.thromres.2021.12.009","volume":"213","author":"JJ Fuster","year":"2022","unstructured":"Fuster JJ. Clonal hematopoiesis and cardiovascular disease in cancer patients and survivors. Thromb Res. 2022;213:S107\u2013s12.","journal-title":"Thromb Res"},{"key":"2030_CR36","doi-asserted-by":"publisher","first-page":"370","DOI":"10.1001\/jamaoncol.2015.6053","volume":"2","author":"EM Swisher","year":"2016","unstructured":"Swisher EM, Harrell MI, Norquist BM, Walsh T, Brady M, Lee M, et al. Somatic mosaic mutations in PPM1D and TP53 in the blood of women with ovarian carcinoma. JAMA Oncol. 2016;2:370\u20132.","journal-title":"JAMA Oncol"},{"key":"2030_CR37","doi-asserted-by":"publisher","first-page":"1114","DOI":"10.1038\/bjc.2015.79","volume":"112","author":"A Zajkowicz","year":"2015","unstructured":"Zajkowicz A, Butkiewicz D, Drosik A, Giglok M, Suwi\u0144ski R, Rusin M. Truncating mutations of PPM1D are found in blood DNA samples of lung cancer patients. Br J Cancer. 2015;112:1114\u201320.","journal-title":"Br J Cancer"},{"key":"2030_CR38","doi-asserted-by":"publisher","first-page":"2574","DOI":"10.1182\/blood.2019004664","volume":"136","author":"P Danek","year":"2020","unstructured":"Danek P, Kardosova M, Janeckova L, Karkoulia E, Vanickova K, Fabisik M, et al. \u03b2-Catenin-TCF\/LEF signaling promotes steady-state and emergency granulopoiesis via G-CSF receptor upregulation. Blood. 2020;136:2574\u201387.","journal-title":"Blood"},{"key":"2030_CR39","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1016\/j.jim.2009.06.008","volume":"347","author":"Y Hu","year":"2009","unstructured":"Hu Y, Smyth GK. ELDA: extreme limiting dilution analysis for comparing depleted and enriched populations in stem cell and other assays. J Immunol Methods. 2009;347:70\u20138.","journal-title":"J Immunol Methods"},{"key":"2030_CR40","first-page":"923","volume":"30","author":"Y Liao","year":"2014","unstructured":"Liao Y, Smyth GK, Shi W. featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinforma (Oxf, Engl). 2014;30:923\u201330.","journal-title":"Bioinforma (Oxf, Engl)"},{"key":"2030_CR41","doi-asserted-by":"publisher","first-page":"15545","DOI":"10.1073\/pnas.0506580102","volume":"102","author":"A Subramanian","year":"2005","unstructured":"Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA. 2005;102:15545\u201350.","journal-title":"Proc Natl Acad Sci USA"},{"key":"2030_CR42","doi-asserted-by":"publisher","first-page":"2622","DOI":"10.3390\/ijms22052622","volume":"22","author":"\u00c1 Bartha","year":"2021","unstructured":"Bartha \u00c1, Gy\u0151rffy B. TNMplot.com: A Web Tool for the Comparison of Gene Expression in Normal, Tumor and Metastatic Tissues. Int J Mol Sci. 2021;22:2622.","journal-title":"Int J Mol Sci"},{"key":"2030_CR43","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-35089-5","volume":"13","author":"Z Andrysik","year":"2022","unstructured":"Andrysik Z, Sullivan KD, Kieft JS, Espinosa JM. PPM1D suppresses p53-dependent transactivation and cell death by inhibiting the Integrated Stress Response. Nat Commun. 2022;13:7400.","journal-title":"Nat Commun"},{"key":"2030_CR44","doi-asserted-by":"publisher","first-page":"879","DOI":"10.1016\/j.stem.2018.05.003","volume":"22","author":"C Baumgartner","year":"2018","unstructured":"Baumgartner C, Toifl S, Farlik M, Halbritter F, Scheicher R, Fischer I, et al. An ERK-dependent feedback mechanism prevents hematopoietic stem cell exhaustion. Cell Stem Cell. 2018;22:879\u201392.e6.","journal-title":"Cell Stem Cell"},{"key":"2030_CR45","doi-asserted-by":"publisher","first-page":"1312","DOI":"10.1007\/s12015-021-10131-z","volume":"17","author":"H Fernandes","year":"2021","unstructured":"Fernandes H, Moura J, Carvalho E. mTOR signaling as a regulator of hematopoietic stem cell fate. Stem Cell Rev Rep. 2021;17:1312\u201322.","journal-title":"Stem Cell Rev Rep"},{"key":"2030_CR46","doi-asserted-by":"publisher","first-page":"2747","DOI":"10.1101\/gad.313104","volume":"18","author":"A Wilson","year":"2004","unstructured":"Wilson A, Murphy MJ, Oskarsson T, Kaloulis K, Bettess MD, Oser GM, et al. c-Myc controls the balance between hematopoietic stem cell self-renewal and differentiation. Genes Dev. 2004;18:2747\u201363.","journal-title":"Genes Dev"},{"key":"2030_CR47","doi-asserted-by":"publisher","first-page":"437","DOI":"10.1038\/ni.2572","volume":"14","author":"B Will","year":"2013","unstructured":"Will B, Vogler TO, Bartholdy B, Garrett-Bakelman F, Mayer J, Barreyro L, et al. Satb1 regulates the self-renewal of hematopoietic stem cells by promoting quiescence and repressing differentiation commitment. Nat Immunol. 2013;14:437\u201345.","journal-title":"Nat Immunol"},{"key":"2030_CR48","doi-asserted-by":"publisher","first-page":"26427","DOI":"10.1074\/jbc.M109.014845","volume":"284","author":"MA McGill","year":"2009","unstructured":"McGill MA, Dho SE, Weinmaster G, McGlade CJ. Numb regulates post-endocytic trafficking and degradation of Notch1. J Biol Chem. 2009;284:26427\u201338.","journal-title":"J Biol Chem"},{"key":"2030_CR49","doi-asserted-by":"publisher","first-page":"23196","DOI":"10.1074\/jbc.M302827200","volume":"278","author":"MA McGill","year":"2003","unstructured":"McGill MA, McGlade CJ. Mammalian numb proteins promote Notch1 receptor ubiquitination and degradation of the Notch1 intracellular domain. J Biol Chem. 2003;278:23196\u2013203.","journal-title":"J Biol Chem"},{"key":"2030_CR50","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2017.474","volume":"8","author":"L Racioppi","year":"2017","unstructured":"Racioppi L, Lento W, Huang W, Arvai S, Doan PL, Harris JR, et al. Calcium\/calmodulin-dependent kinase kinase 2 regulates hematopoietic stem and progenitor cell regeneration. Cell Death Dis. 2017;8:e3076.","journal-title":"Cell Death Dis"},{"key":"2030_CR51","doi-asserted-by":"publisher","first-page":"35108","DOI":"10.1074\/jbc.M503912200","volume":"280","author":"H Tokumitsu","year":"2005","unstructured":"Tokumitsu H, Hatano N, Inuzuka H, Sueyoshi Y, Yokokura S, Ichimura T, et al. Phosphorylation of Numb family proteins. Possible involvement of Ca2+\/calmodulin-dependent protein kinases. J Biol Chem. 2005;280:35108\u201318.","journal-title":"J Biol Chem"},{"key":"2030_CR52","doi-asserted-by":"publisher","first-page":"374","DOI":"10.1126\/scitranslmed.aaj2025","volume":"9","author":"SS Chung","year":"2017","unstructured":"Chung SS, Eng WS, Hu W, Khalaj M, Garrett-Bakelman FE, Tavakkoli M, et al. CD99 is a therapeutic target on disease stem cells in myeloid malignancies. Sci Transl Med. 2017;9:374.","journal-title":"Sci Transl Med"},{"key":"2030_CR53","doi-asserted-by":"publisher","first-page":"194","DOI":"10.1038\/s12276-022-00735-x","volume":"54","author":"N Zhang","year":"2022","unstructured":"Zhang N, Shen Y, Li H, Chen Y, Zhang P, Lou S, et al. The m6A reader IGF2BP3 promotes acute myeloid leukemia progression by enhancing RCC2 stability. Exp Mol Med. 2022;54:194\u2013205.","journal-title":"Exp Mol Med"},{"key":"2030_CR54","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1038\/s41375-021-01346-7","volume":"36","author":"TM Tran","year":"2022","unstructured":"Tran TM, Philipp J, Bassi JS, Nibber N, Draper JM, Lin TL, et al. The RNA-binding protein IGF2BP3 is critical for MLL-AF4-mediated leukemogenesis. Leukemia. 2022;36:68\u201379.","journal-title":"Leukemia"},{"key":"2030_CR55","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1042\/BSR20204037","volume":"41","author":"B Zhang","year":"2021","unstructured":"Zhang B, Yang L, Wang X, Fu D. Identification of survival-related alternative splicing signatures in acute myeloid leukemia. Biosci Rep. 2021;41:7.","journal-title":"Biosci Rep"},{"key":"2030_CR56","doi-asserted-by":"publisher","first-page":"2679","DOI":"10.1182\/blood-2019-129427","volume":"134","author":"M M Hosseini","year":"2019","unstructured":"M Hosseini M, Lin H-Y, Dewson G, Vivier R, Agarwal A. Marcks is a critical downstream mediator of IL-1-Driven AML progression. Blood 2019;134:2679.","journal-title":"Blood"},{"key":"2030_CR57","doi-asserted-by":"publisher","first-page":"1769","DOI":"10.1038\/s41375-022-01577-2","volume":"36","author":"AC Menezes","year":"2022","unstructured":"Menezes AC, Jones R, Shrestha A, Nicholson R, Leckenby A, Azevedo A, et al. Increased expression of RUNX3 inhibits normal human myeloid development. Leukemia 2022;36:1769\u201380.","journal-title":"Leukemia"},{"key":"2030_CR58","doi-asserted-by":"publisher","DOI":"10.1186\/s40001-022-00740-w","volume":"27","author":"P Chang","year":"2022","unstructured":"Chang P, Chen S, Chang X, Zhu J, Tang Q, Ma L. EXTL3 could serve as a potential biomarker of prognosis and immunotherapy for prostate cancer and its potential mechanisms. Eur J Med Res. 2022;27:115.","journal-title":"Eur J Med Res"},{"key":"2030_CR59","doi-asserted-by":"publisher","first-page":"1787","DOI":"10.1038\/s41375-020-0732-1","volume":"34","author":"JR Sinnakannu","year":"2020","unstructured":"Sinnakannu JR, Lee KL, Cheng S, Li J, Yu M, Tan SP, et al. SRSF1 mediates cytokine-induced impaired imatinib sensitivity in chronic myeloid leukemia. Leukemia. 2020;34:1787\u201398.","journal-title":"Leukemia"},{"key":"2030_CR60","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-34558-1","volume":"13","author":"H Okuda","year":"2022","unstructured":"Okuda H, Miyamoto R, Takahashi S, Kawamura T, Ichikawa J, Harada I, et al. RNA-binding proteins of KHDRBS and IGF2BP families control the oncogenic activity of MLL-AF4. Nat Commun. 2022;13:6688.","journal-title":"Nat Commun"},{"key":"2030_CR61","doi-asserted-by":"publisher","DOI":"10.1038\/s41420-022-00844-6","volume":"8","author":"M Du","year":"2022","unstructured":"Du M, Peng Y, Li Y, Sun W, Zhu H, Wu J, et al. MYC-activated RNA N6-methyladenosine reader IGF2BP3 promotes cell proliferation and metastasis in nasopharyngeal carcinoma. Cell Death Discov. 2022;8:53.","journal-title":"Cell Death Discov"},{"key":"2030_CR62","doi-asserted-by":"publisher","first-page":"664","DOI":"10.1016\/j.semcancer.2022.03.025","volume":"86","author":"W Li","year":"2022","unstructured":"Li W, Deng X, Chen J. RNA-binding proteins in regulating mRNA stability and translation: roles and mechanisms in cancer. Semin Cancer Biol. 2022;86:664\u201377.","journal-title":"Semin Cancer Biol"},{"key":"2030_CR63","doi-asserted-by":"publisher","first-page":"406","DOI":"10.1038\/nature11725","volume":"493","author":"E Ruark","year":"2013","unstructured":"Ruark E, Snape K, Humburg P, Loveday C, Bajrami I, Brough R, et al. Mosaic PPM1D mutations are associated with predisposition to breast and ovarian cancer. Nature. 2013;493:406\u201310.","journal-title":"Nature."},{"key":"2030_CR64","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-28198-8","volume":"13","author":"P Khadka","year":"2022","unstructured":"Khadka P, Reitman ZJ, Lu S, Buchan G, Gionet G, Dubois F, et al. PPM1D mutations are oncogenic drivers of de novo diffuse midline glioma formation. Nat Commun. 2022;13:604.","journal-title":"Nat Commun"},{"key":"2030_CR65","doi-asserted-by":"publisher","first-page":"994","DOI":"10.1038\/s43018-022-00403-z","volume":"3","author":"F Dubois","year":"2022","unstructured":"Dubois F, Shapira O, Greenwald NF, Zack T, Wala J, Tsai JW, et al. Structural variants shape driver combinations and outcomes in pediatric high-grade glioma. Nat Cancer. 2022;3:994\u20131011.","journal-title":"Nat Cancer"},{"key":"2030_CR66","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1038\/nrg2269","volume":"9","author":"KW Orford","year":"2008","unstructured":"Orford KW, Scadden DT. Deconstructing stem cell self-renewal: genetic insights into cell-cycle regulation. Nat Rev Genet. 2008;9:115\u201328.","journal-title":"Nat Rev Genet"},{"key":"2030_CR67","doi-asserted-by":"publisher","first-page":"473","DOI":"10.1038\/s41586-018-0497-0","volume":"561","author":"H Lee-Six","year":"2018","unstructured":"Lee-Six H, \u00d8bro NF, Shepherd MS, Grossmann S, Dawson K, Belmonte M, et al. Population dynamics of normal human blood inferred from somatic mutations. Nature 2018;561:473\u20138.","journal-title":"Nature"},{"key":"2030_CR68","doi-asserted-by":"publisher","first-page":"709","DOI":"10.1083\/jcb.201102131","volume":"195","author":"EM Pietras","year":"2011","unstructured":"Pietras EM, Warr MR, Passegu\u00e9 E. Cell cycle regulation in hematopoietic stem cells. J Cell Biol. 2011;195:709\u201320.","journal-title":"J Cell Biol"},{"key":"2030_CR69","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1016\/j.cell.2008.07.049","volume":"135","author":"F Wirtz-Peitz","year":"2008","unstructured":"Wirtz-Peitz F, Nishimura T, Knoblich JA. Linking cell cycle to asymmetric division: Aurora-A phosphorylates the Par complex to regulate Numb localization. Cell .2008;135:161\u201373.","journal-title":"Cell"},{"key":"2030_CR70","doi-asserted-by":"publisher","first-page":"993","DOI":"10.1021\/acsptsci.2c00147","volume":"5","author":"V Clausse","year":"2022","unstructured":"Clausse V, Fang Y, Tao D, Tagad HD, Sun H, Wang Y, et al. Discovery of novel small-molecule scaffolds for the inhibition and activation of WIP1 Phosphatase from a rapidfire mass spectrometry high-throughput screen. ACS Pharmacol Transl Sci. 2022;5:993\u20131006.","journal-title":"ACS Pharmacol Transl Sci"},{"key":"2030_CR71","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-30463-9","volume":"13","author":"PG Miller","year":"2022","unstructured":"Miller PG, Sathappa M, Moroco JA. Allosteric inhibition of PPM1D serine\/threonine phosphatase via an altered conformational state. Nat Commun. 2022;13:3778.","journal-title":"Nat Commun"}],"container-title":["Leukemia"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41375-023-02030-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41375-023-02030-8","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41375-023-02030-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,3]],"date-time":"2023-11-03T08:03:10Z","timestamp":1698998590000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41375-023-02030-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,9,14]]},"references-count":71,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2023,11]]}},"alternative-id":["2030"],"URL":"https:\/\/doi.org\/10.1038\/s41375-023-02030-8","relation":{},"ISSN":["0887-6924","1476-5551"],"issn-type":[{"value":"0887-6924","type":"print"},{"value":"1476-5551","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,9,14]]},"assertion":[{"value":"22 June 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"31 August 2023","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 September 2023","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 September 2023","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}