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

Abstract

Summary Somatic PTPN11 mutations cause juvenile myelomonocytic leukemia (JMML). Germ-line 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 up-regulation of miR-223 and miR-15a. Similarly, miR-223 and miR-15a were up-regulated 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. Micro-RNA 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 micro-RNA dysregulation, establishing a genotype-phenotype association for JMML and providing novel therapeutic targets.

Li–Fraumeni Syndrome Disease Model: A Platform to Develop Precision Cancer Therapy Targeting Oncogenic p53

“…Patient-derived iPSCs have been used to model various diseases, including long QT syndrome (LQTS) [159, 160], alpha-1 antitrypsin (AAT) deficiency [161, 162], familial dysautonomia (FD) [163, 164] Diamond-Blackfan anemia (DBA) [165–167], familial Alzheimer’s disease [168] and RASopathy disorders [169, 170], to name a few. Successful disease modeling not only sheds light on disease mechanisms but also leads to the development of in vitro assays – readouts of disease-associated phenotype – that facilitate high-throughput drug screening.…”

Patient-derived induced pluripotent stem cells in cancer research and precision oncology

“…These are limited to myeloid malignancies, such as myeloproliferative neoplasms (MPNs)—including chronic myeloid leukemia, polycythemia vera and primary myelofibrosis—myelodysplastic syndromes (MDSs) and the MDS–MPN overlap syndrome, juvenile myelomonocytic leukemia 25–32 . iPSCs from patients with these disorders have shown cellular and molecular phenotypes characteristic of the underlying disorders, such as altered differentiation potential, hematopoietic cell colony formation, cell proliferation and viability, gene expression changes, signaling aberrations and drug sensitivities.…”

Yolk sac erythromyeloid progenitors expressing gain of function PTPN11 have functional features of JMML but are not sufficient to cause disease in mice

“…Second, JMML patients frequently acquire their disease-initiating mutations in utero (Matsuda et al, 2010; Stieglitz et al, 2015). Finally, several studies have successfully modelled JMML using patient-derived iPSCs, whose differentiation mimics that of HSC-independent YS hematopoiesis (Gandre-Babbe et al, 2013; Mulero-Navarro et al, 2015; Vanhee et al, 2015; Buchrieser et al, 2017). This reasoning prompted us to hypothesize that expression of JMML-initiating mutations in embryonic HSC-independent progenitors would be sufficient for disease development (Chan and Yoder, 2013).…”

“…Several lines of evidence—in addition to the disease's in utero origin and fetal characteristics—suggest that EMPs may contribute to the pathogenesis of this disease. JMML has been successfully modelled with patient-derived induced pluripotent stem cells (iPSCs) (Gandre-Babbe et al, 2013; Mulero-Navarro et al, 2015). However, iPSCs cannot give rise to HSCs and can only recapitulate YS-like HSC-independent hematopoiesis (Vanhee et al, 2015; Buchrieser et al, 2017).…”