Abstract
Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative neoplasm of young children initiated by mutations that deregulate cytokine receptor signaling. Studies of JMML are constrained by limited access to patient tissues. We generated induced pluripotent stem cells (iPSCs) from malignant cells of two JMML patients with somatic heterozygous p.E76K missense mutations in PTPN11, which encodes SHP-2, a nonreceptor tyrosine phosphatase. In vitro differentiation of JMML iPSCs produced myeloid cells with increased proliferative capacity, constitutive activation of granulocyte macrophage colony-stimulating factor (GM-CSF), and enhanced STAT5/ERK phosphorylation, similar to primary JMML cells from patients. Pharmacological inhibition of MEK kinase in iPSC-derived JMML cells reduced their GM-CSF independence, providing rationale for a potential targeted therapy. Our studies offer renewable sources of biologically relevant human cells in which to explore the pathophysiology and treatment of JMML. More generally, we illustrate the utility of iPSCs for in vitro modeling of a human malignancy.
Publication types
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Clinical Trial
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Cell Differentiation / drug effects
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Cell Differentiation / genetics
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Cohort Studies
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Extracellular Signal-Regulated MAP Kinases / genetics
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Female
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Granulocyte-Macrophage Colony-Stimulating Factor / pharmacology
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Heterozygote
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Humans
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Induced Pluripotent Stem Cells / metabolism*
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Induced Pluripotent Stem Cells / pathology
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Leukemia, Myelomonocytic, Juvenile / genetics
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Leukemia, Myelomonocytic, Juvenile / metabolism*
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Leukemia, Myelomonocytic, Juvenile / pathology
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Male
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Mutation, Missense*
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Neoplastic Stem Cells / metabolism*
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Neoplastic Stem Cells / pathology
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Phosphorylation
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Protein Tyrosine Phosphatase, Non-Receptor Type 1 / genetics
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Protein Tyrosine Phosphatase, Non-Receptor Type 1 / metabolism*
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STAT5 Transcription Factor / genetics
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STAT5 Transcription Factor / metabolism
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Tumor Cells, Cultured
Substances
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STAT5 Transcription Factor
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Granulocyte-Macrophage Colony-Stimulating Factor
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Extracellular Signal-Regulated MAP Kinases
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PTPN1 protein, human
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Protein Tyrosine Phosphatase, Non-Receptor Type 1