Differential Sensitivity to JAK Inhibitory Drugs by Isogenic Human Erythroblasts and Hematopoietic Progenitors Generated from Patient-Specific Induced Pluripotent Stem Cells

Authors

  • Zhaohui Ye,

    Corresponding author
    1. Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
    2. Stem Cell Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
    • Correspondence: Zhaohui Ye, Ph.D., Division of Hematology, 720 Rutland Avenue, Ross Research Building, Room 1032, Baltimore, Maryland 21205, USA. Telephone: +1–410-502–6686; Fax: +1–410-955-0185; email: zye@jhmi.edu; or Linzhao Cheng, Ph.D., Edward Miller Research Building 747, 733 North Broadway, Baltimore, Maryland 21205, USA. Telephone: +1–410-614–6958; Fax: +1–443 287–5611; email: lcheng2@jhmi.edu

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  • Cyndi F. Liu,

    1. Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
    2. Stem Cell Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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  • Lucie Lanikova,

    1. Hematology Division, University of Utah and Veterans Affairs Medical Center, Salt Lake City, Utah, USA
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  • Sarah N. Dowey,

    1. Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
    2. Stem Cell Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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  • Chaoxia He,

    1. Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
    2. Stem Cell Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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  • Xiaosong Huang,

    1. Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
    2. Stem Cell Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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  • Robert A. Brodsky,

    1. Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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  • Jerry L. Spivak,

    1. Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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  • Josef T. Prchal,

    1. Hematology Division, University of Utah and Veterans Affairs Medical Center, Salt Lake City, Utah, USA
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  • Linzhao Cheng

    Corresponding author
    1. Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
    2. Stem Cell Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
    • Correspondence: Zhaohui Ye, Ph.D., Division of Hematology, 720 Rutland Avenue, Ross Research Building, Room 1032, Baltimore, Maryland 21205, USA. Telephone: +1–410-502–6686; Fax: +1–410-955-0185; email: zye@jhmi.edu; or Linzhao Cheng, Ph.D., Edward Miller Research Building 747, 733 North Broadway, Baltimore, Maryland 21205, USA. Telephone: +1–410-614–6958; Fax: +1–443 287–5611; email: lcheng2@jhmi.edu

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Abstract

Disease-specific induced pluripotent stem cells (iPSCs) provide an unprecedented opportunity to establish novel disease models and accelerate drug development using distinct tissue target cells generated from isogenic iPSC lines with and without disease-causing mutations. To realize the potential of iPSCs in modeling acquired diseases which are usually heterogeneous, we have generated multiple iPSC lines including two lines that are JAK2-wild-type and four lines homozygous for JAK2-V617F somatic mutation from a single polycythemia vera (PV) patient blood. In vitro differentiation of the same patient-derived iPSC lines have demonstrated the differential contributions of their parental hematopoietic clones to the abnormal erythropoiesis including the formation of endogenous erythroid colonies. This iPSC approach thus may provide unique and valuable insights into the genetic events responsible for disease development. To examine the potential of iPSCs in drug testing, we generated isogenic hematopoietic progenitors and erythroblasts from the same iPSC lines derived from PV patients and normal donors. Their response to three clinical JAK inhibitors, INCB018424 (Ruxolitinib), TG101348 (SAR302503), and the more recent CYT387 was evaluated. All three drugs similarly inhibited erythropoiesis from normal and PV iPSC lines containing the wild-type JAK2 genotype, as well as those containing a homozygous or heterozygous JAK2-V617F activating mutation that showed increased erythropoiesis without a JAK inhibitor. However, the JAK inhibitors had less inhibitory effect on the self-renewal of CD34+ hematopoietic progenitors. The iPSC-mediated disease modeling thus underlies the ineffectiveness of the current JAK inhibitors and provides a modeling system to develop better targeted therapies for the JAK2 mutated hematopoiesis. Stem Cells 2014;32:269–278

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