Myeloid Dysregulation in a Human Induced Pluripotent Stem Cell Model of PTPN11-Associated Juvenile Myelomonocytic Leukemia

Overview

Journal Cell Rep

Publisher Cell Press

Specialties Biology
Cell Biology
Molecular Biology

Date 2015 Oct 13

PMID 26456833

Citations 47

Authors

Sonia Mulero-Navarro

Ana Sevilla

Angel C Roman

Dung-Fang Lee

Sunita L DSouza

Sherly Pardo

Ilan Riess

Jie Su

Ninette Cohen

Christoph Schaniel

Nelson A Rodriguez

Alessia Baccarini

Brian D Brown

Helene Cave

Aurelie 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

Soon will be listed here.

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.

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