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 language | English |
|---|---|
| Article number | 2071 |
| Pages (from-to) | 504-515 |
| Number of pages | 12 |
| Journal | Cell Reports |
| Volume | 13 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - Oct 20 2015 |
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ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
Cite this
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 journal › Article
}
TY - JOUR
T1 - Myeloid Dysregulation in a Human Induced Pluripotent Stem Cell Model of PTPN11-Associated Juvenile Myelomonocytic Leukemia
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.
PY - 2015/10/20
Y1 - 2015/10/20
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.
AB - 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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UR - http://www.scopus.com/inward/citedby.url?scp=84944674356&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2015.09.019
DO - 10.1016/j.celrep.2015.09.019
M3 - Article
AN - SCOPUS:84944674356
VL - 13
SP - 504
EP - 515
JO - Cell Reports
JF - Cell Reports
SN - 2211-1247
IS - 3
M1 - 2071
ER -