Myeloid Dysregulation in a Human Induced Pluripotent Stem Cell Model of PTPN11-Associated Juvenile Myelomonocytic Leukemia.
| Title: | Myeloid Dysregulation in a Human Induced Pluripotent Stem Cell Model of PTPN11-Associated Juvenile Myelomonocytic Leukemia. |
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| Authors: | Mulero-Navarro S; The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.; Sevilla A; The Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.; Roman AC; Instituto Cajal-Consejo Superior de Investigaciones Científicas, Madrid 28002, Spain.; Lee DF; The Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.; D'Souza SL; The Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.; Pardo S; Department of Biochemistry, University of Puerto Rico School of Medicine, San Juan, PR 00936, USA.; Riess I; Buck Institute for Research on Aging, Novato, CA 94945, USA.; Su J; The Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.; Cohen N; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.; Schaniel C; The Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.; Rodriguez NA; The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.; Baccarini A; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.; Brown BD; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.; Cavé H; Département de Génétique, Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpital Robert Debré, 75019 Paris, France; INSERM UMR_S1131, Institut Universitaire d'Hématologie, Université Paris Diderot, Paris-Sorbonne-Cité, 75205 Paris, France.; Caye A; Département de Génétique, Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpital Robert Debré, 75019 Paris, France; INSERM UMR_S1131, Institut Universitaire d'Hématologie, Université Paris Diderot, Paris-Sorbonne-Cité, 75205 Paris, France.; Strullu M; Département de Génétique, Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpital Robert Debré, 75019 Paris, France; INSERM UMR_S1131, Institut Universitaire d'Hématologie, Université Paris Diderot, Paris-Sorbonne-Cité, 75205 Paris, France.; Yalcin S; Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.; Park CY; Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.; Dhandapany PS; The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.; Yongchao G; Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.; Edelmann L; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.; Bahieg S; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.; Raynal P; Université Paul Sabatier-M2CHRNRS, 31062 Toulouse, France.; Flex E; Dipartimento di Ematologia, Oncologia e Medicina Molecolare, Istituto Superiore di Sanità, Rome 00161, Italy.; Tartaglia M; Dipartimento di Ematologia, Oncologia e Medicina Molecolare, Istituto Superiore di Sanità, Rome 00161, Italy; Area di Ricerca 'Malattie Genetiche e Malattie Rare,' Ospedale Pediatrico Bambino Gesù, Rome 00165, Italy.; Moore KA; The Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.; Lemischka IR; The Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.; Gelb BD; The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: bruce.gelb@mssm.edu. |
| Source: | Cell reports [Cell Rep] 2015 Oct 20; Vol. 13 (3), pp. 504-515. Date of Electronic Publication: 2015 Oct 08. |
| Publication Type: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| Language: | English |
| Journal Info: | Publisher: Cell Press Country of Publication: United States NLM ID: 101573691 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2211-1247 (Electronic) NLM ISO Abbreviation: Cell Rep Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: [Cambridge, MA] : Cell Press, c 2012- |
| MeSH Terms: | Induced Pluripotent Stem Cells/*cytology ; Leukemia, Myelomonocytic, Juvenile/*metabolism ; Myeloid Cells/*cytology ; Protein Tyrosine Phosphatase, Non-Receptor Type 11/*genetics ; Sialic Acid Binding Ig-like Lectin 3/*metabolism; Induced Pluripotent Stem Cells/metabolism ; Leukemia, Myelomonocytic, Juvenile/genetics ; Leukemia, Myelomonocytic, Juvenile/pathology ; MicroRNAs/genetics ; Myeloid Cells/metabolism ; Sialic Acid Binding Ig-like Lectin 3/genetics ; Cells, Cultured ; HEK293 Cells ; Humans ; Mutation ; Up-Regulation |
| Abstract: | Somatic PTPN11 mutations cause juvenile myelomonocytic leukemia (JMML). Germline PTPN11 defects cause Noonan syndrome (NS), and specific inherited mutations cause NS/JMML. Here, we report that hematopoietic cells differentiated from human induced pluripotent stem cells (hiPSCs) harboring NS/JMML-causing PTPN11 mutations recapitulated JMML features. hiPSC-derived NS/JMML myeloid cells exhibited increased signaling through STAT5 and upregulation of miR-223 and miR-15a. Similarly, miR-223 and miR-15a were upregulated in 11/19 JMML bone marrow mononuclear cells harboring PTPN11 mutations, but not those without PTPN11 defects. Reducing miR-223's function in NS/JMML hiPSCs normalized myelogenesis. MicroRNA target gene expression levels were reduced in hiPSC-derived myeloid cells as well as in JMML cells with PTPN11 mutations. Thus, studying an inherited human cancer syndrome with hiPSCs illuminated early oncogenesis prior to the accumulation of secondary genomic alterations, enabling us to discover microRNA dysregulation, establishing a genotype-phenotype association for JMML and providing therapeutic targets.; (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.) |
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| Grant Information: | HL071207 United States HL NHLBI NIH HHS; HL113499 United States HL NHLBI NIH HHS; R01 HL113499 United States HL NHLBI NIH HHS; R01 HL071207 United States HL NHLBI NIH HHS; GGP13107 Italy TI_ Telethon |
| Substance Nomenclature: | 0 (MicroRNAs); EC 3.1.3.48 (Protein Tyrosine Phosphatase, Non-Receptor Type 11); 0 (Sialic Acid Binding Ig-like Lectin 3); 0 (MIRN15 microRNA, human); 0 (MIR223, human); EC 3.1.3.48 (PTPN11 protein, human) |
| Entry Date(s): | Date Created: 20151013 Date Completed: 20160804 Latest Revision: 20260127 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC4618050 |
| DOI: | 10.1016/j.celrep.2015.09.019 |
| PMID: | 26456833 |
| Database: | MEDLINE |
Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't