title: Myeloid Dysregulation in a Human Induced Pluripotent Stem Cell Model of PTPN11-Associated Juvenile Myelomonocytic Leukemia.
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.
authors.affiliation: 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.
authors.forename: Sonia
authors.initials: S
authors.lastname: Mulero-Navarro
authors.affiliation: 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.
authors.forename: Ana
authors.initials: A
authors.lastname: Sevilla
authors.affiliation: Instituto Cajal-Consejo Superior de Investigaciones Científicas, Madrid 28002, Spain.
authors.forename: Angel C
authors.initials: AC
authors.lastname: Roman
authors.affiliation: 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.
authors.forename: Dung-Fang
authors.initials: DF
authors.lastname: Lee
authors.affiliation: 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.
authors.forename: Sunita L
authors.initials: SL
authors.lastname: D'Souza
authors.affiliation: Department of Biochemistry, University of Puerto Rico School of Medicine, San Juan, PR 00936, USA.
authors.forename: Sherly
authors.initials: S
authors.lastname: Pardo
authors.affiliation: Buck Institute for Research on Aging, Novato, CA 94945, USA.
authors.forename: Ilan
authors.initials: I
authors.lastname: Riess
authors.affiliation: 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.
authors.forename: Jie
authors.initials: J
authors.lastname: Su
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Ninette
authors.initials: N
authors.lastname: Cohen
authors.affiliation: 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.
authors.forename: Christoph
authors.initials: C
authors.lastname: Schaniel
authors.affiliation: The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Nelson A
authors.initials: NA
authors.lastname: Rodriguez
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Alessia
authors.initials: A
authors.lastname: Baccarini
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Brown
authors.affiliation: 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.
authors.forename: Hélène
authors.initials: H
authors.lastname: Cavé
authors.affiliation: 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.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Caye
authors.affiliation: 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.
authors.forename: Marion
authors.initials: M
authors.lastname: Strullu
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Safak
authors.initials: S
authors.lastname: Yalcin
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Christopher Y
authors.initials: CY
authors.lastname: Park
authors.affiliation: The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Perundurai S
authors.initials: PS
authors.lastname: Dhandapany
authors.affiliation: Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Ge
authors.initials: G
authors.lastname: Yongchao
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Edelmann
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Sawsan
authors.initials: S
authors.lastname: Bahieg
authors.affiliation: Université Paul Sabatier-M2CHRNRS, 31062 Toulouse, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Raynal
authors.affiliation: Dipartimento di Ematologia, Oncologia e Medicina Molecolare, Istituto Superiore di Sanità, Rome 00161, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Flex
authors.affiliation: 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.
authors.forename: Marco
authors.initials: M
authors.lastname: Tartaglia
authors.affiliation: 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.
authors.forename: Kateri A
authors.initials: KA
authors.lastname: Moore
authors.affiliation: 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.
authors.forename: Ihor R
authors.initials: IR
authors.lastname: Lemischka
authors.affiliation: 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.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Gelb
mesh_terms: D002478:Cells, Cultured; D057809:HEK293 Cells; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism; D054429:Leukemia, Myelomonocytic, Juvenile / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics; D009154:Mutation; D022423:Myeloid Cells / Q000166:cytology* / Q000378:metabolism; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics*; D063268:Sialic Acid Binding Ig-like Lectin 3 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D035683:MicroRNAs; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D063268:Sialic Acid Binding Ig-like Lectin 3; C505361:MIRN15 microRNA, human; C525067:MIR223, human; C516724:PTPN11 protein, human