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 & 8 others Lisa Edelmann, Sawsan Bahieg, Patrick Raynal, Elisabetta Flex, Marco Tartaglia, Kateri A. Moore, Ihor R. Lemischka, Bruce D. Gelb

Research output: Contribution to journalArticle

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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. Using hiPSCs, Mulero-Navarro et al. recapitulate the principal features of JMML and show dysregulation in myeloid cells in the context of NS. Moreover, they identify upregulation of two microRNAs as potential biomarkers in JMML mononuclear cells, and this upregulation distinguishes JMML caused by PTPN11 mutations from other genetic forms of this disease.

Original languageEnglish
Article number2071
Pages (from-to)504-515
Number of pages12
JournalCell Reports
Volume13
Issue number3
DOIs
Publication statusPublished - Oct 20 2015

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Juvenile Myelomonocytic Leukemia
Induced Pluripotent Stem Cells
Stem cells
MicroRNAs
Noonan Syndrome
Defects
Mutation
Biomarkers
Myeloid Cells
Gene expression
Bone
Up-Regulation
Association reactions
Inborn Genetic Diseases
Genetic Association Studies
Bone Marrow Cells

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Mulero-Navarro, S., Sevilla, A., Roman, A. C., Lee, D. F., D'Souza, S. L., Pardo, S., ... Gelb, B. D. (2015). Myeloid Dysregulation in a Human Induced Pluripotent Stem Cell Model of PTPN11-Associated Juvenile Myelomonocytic Leukemia. Cell Reports, 13(3), 504-515. [2071]. https://doi.org/10.1016/j.celrep.2015.09.019

Myeloid Dysregulation in a Human Induced Pluripotent Stem Cell Model of PTPN11-Associated Juvenile Myelomonocytic Leukemia. / Mulero-Navarro, Sonia; Sevilla, Ana; Roman, Angel C.; Lee, Dung Fang; D'Souza, Sunita L.; Pardo, Sherly; Riess, Ilan; Su, Jie; Cohen, Ninette; Schaniel, Christoph; Rodriguez, Nelson A.; Baccarini, Alessia; Brown, Brian D.; Cavé, Hélène; Caye, Aurélie; Strullu, Marion; Yalcin, Safak; Park, Christopher Y.; Dhandapany, Perundurai S.; Yongchao, Ge; Edelmann, Lisa; Bahieg, Sawsan; Raynal, Patrick; Flex, Elisabetta; Tartaglia, Marco; Moore, Kateri A.; Lemischka, Ihor R.; Gelb, Bruce D.

In: Cell Reports, Vol. 13, No. 3, 2071, 20.10.2015, p. 504-515.

Research output: Contribution to journalArticle

Mulero-Navarro, S, Sevilla, A, Roman, AC, Lee, DF, D'Souza, SL, Pardo, S, Riess, I, Su, J, Cohen, N, Schaniel, C, Rodriguez, NA, Baccarini, A, Brown, BD, Cavé, H, Caye, A, Strullu, M, Yalcin, S, Park, CY, Dhandapany, PS, Yongchao, G, Edelmann, L, Bahieg, S, Raynal, P, Flex, E, Tartaglia, M, Moore, KA, Lemischka, IR & Gelb, BD 2015, 'Myeloid Dysregulation in a Human Induced Pluripotent Stem Cell Model of PTPN11-Associated Juvenile Myelomonocytic Leukemia', Cell Reports, vol. 13, no. 3, 2071, pp. 504-515. https://doi.org/10.1016/j.celrep.2015.09.019
Mulero-Navarro, Sonia ; Sevilla, Ana ; Roman, Angel C. ; Lee, Dung Fang ; D'Souza, Sunita L. ; Pardo, Sherly ; Riess, Ilan ; Su, Jie ; Cohen, Ninette ; Schaniel, Christoph ; Rodriguez, Nelson A. ; Baccarini, Alessia ; Brown, Brian D. ; Cavé, Hélène ; Caye, Aurélie ; Strullu, Marion ; Yalcin, Safak ; Park, Christopher Y. ; Dhandapany, Perundurai S. ; Yongchao, Ge ; Edelmann, Lisa ; Bahieg, Sawsan ; Raynal, Patrick ; Flex, Elisabetta ; Tartaglia, Marco ; Moore, Kateri A. ; Lemischka, Ihor R. ; Gelb, Bruce D. / Myeloid Dysregulation in a Human Induced Pluripotent Stem Cell Model of PTPN11-Associated Juvenile Myelomonocytic Leukemia. In: Cell Reports. 2015 ; Vol. 13, No. 3. pp. 504-515.
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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. Using hiPSCs, Mulero-Navarro et al. recapitulate the principal features of JMML and show dysregulation in myeloid cells in the context of NS. Moreover, they identify upregulation of two microRNAs as potential biomarkers in JMML mononuclear cells, and this upregulation distinguishes JMML caused by PTPN11 mutations from other genetic forms of this disease.",
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AU - Mulero-Navarro, Sonia

AU - Sevilla, Ana

AU - Roman, Angel C.

AU - Lee, Dung Fang

AU - D'Souza, Sunita L.

AU - Pardo, Sherly

AU - Riess, Ilan

AU - Su, Jie

AU - Cohen, Ninette

AU - Schaniel, Christoph

AU - Rodriguez, Nelson A.

AU - Baccarini, Alessia

AU - Brown, Brian D.

AU - Cavé, Hélène

AU - Caye, Aurélie

AU - Strullu, Marion

AU - Yalcin, Safak

AU - Park, Christopher Y.

AU - Dhandapany, Perundurai S.

AU - Yongchao, Ge

AU - Edelmann, Lisa

AU - Bahieg, Sawsan

AU - Raynal, Patrick

AU - Flex, Elisabetta

AU - Tartaglia, Marco

AU - Moore, Kateri A.

AU - Lemischka, Ihor R.

AU - Gelb, Bruce D.

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N2 - 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. Using hiPSCs, Mulero-Navarro et al. recapitulate the principal features of JMML and show dysregulation in myeloid cells in the context of NS. Moreover, they identify upregulation of two microRNAs as potential biomarkers in JMML mononuclear cells, and this upregulation distinguishes JMML caused by PTPN11 mutations from other genetic forms of this disease.

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