Cell Reports (Oct 2015)
Myeloid Dysregulation in a Human Induced Pluripotent Stem Cell Model of PTPN11-Associated Juvenile Myelomonocytic Leukemia
- Sonia Mulero-Navarro,
- Ana Sevilla,
- Angel C. Roman,
- Dung-Fang Lee,
- Sunita L. D’Souza,
- Sherly Pardo,
- Ilan Riess,
- Jie Su,
- Ninette Cohen,
- Christoph Schaniel,
- Nelson A. Rodriguez,
- Alessia Baccarini,
- Brian D. Brown,
- Hélène Cavé,
- Aurélie Caye,
- Marion Strullu,
- Safak Yalcin,
- Christopher Y. Park,
- Perundurai S. Dhandapany,
- Ge Yongchao,
- Lisa Edelmann,
- Sawsan Bahieg,
- Patrick Raynal,
- Elisabetta Flex,
- Marco Tartaglia,
- Kateri A. Moore,
- Ihor R. Lemischka,
- Bruce D. Gelb
Affiliations
- Sonia Mulero-Navarro
- The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Ana Sevilla
- The Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Angel C. Roman
- Instituto Cajal-Consejo Superior de Investigaciones Científicas, Madrid 28002, Spain
- Dung-Fang Lee
- The Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Sunita L. D’Souza
- The Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Sherly Pardo
- Department of Biochemistry, University of Puerto Rico School of Medicine, San Juan, PR 00936, USA
- Ilan Riess
- Buck Institute for Research on Aging, Novato, CA 94945, USA
- Jie Su
- The Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Ninette Cohen
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Christoph Schaniel
- The Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Nelson A. Rodriguez
- The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Alessia Baccarini
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Brian D. Brown
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Hélène Cavé
- Département de Génétique, Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpital Robert Debré, 75019 Paris, France
- Aurélie Caye
- Département de Génétique, Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpital Robert Debré, 75019 Paris, France
- Marion Strullu
- Département de Génétique, Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpital Robert Debré, 75019 Paris, France
- Safak Yalcin
- Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
- Christopher Y. Park
- Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
- Perundurai S. Dhandapany
- The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Ge Yongchao
- Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Lisa Edelmann
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Sawsan Bahieg
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Patrick Raynal
- Université Paul Sabatier-M2CHRNRS, 31062 Toulouse, France
- Elisabetta Flex
- Dipartimento di Ematologia, Oncologia e Medicina Molecolare, Istituto Superiore di Sanità, Rome 00161, Italy
- Marco Tartaglia
- Dipartimento di Ematologia, Oncologia e Medicina Molecolare, Istituto Superiore di Sanità, Rome 00161, Italy
- Kateri A. Moore
- The Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Ihor R. Lemischka
- The Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Bruce D. Gelb
- The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- DOI
- https://doi.org/10.1016/j.celrep.2015.09.019
- Journal volume & issue
-
Vol. 13,
no. 3
pp. 504 – 515
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.
