دورية أكاديمية
أعرض في EDS

Differential sensitivity to JAK inhibitory drugs by isogenic human erythroblasts and hematopoietic progenitors generated from patient-specific induced pluripotent stem cells.

التفاصيل البيبلوغرافية
العنوان: Differential sensitivity to JAK inhibitory drugs by isogenic human erythroblasts and hematopoietic progenitors generated from patient-specific induced pluripotent stem cells.
المؤلفون: Ye Z; Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; Stem Cell Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Liu CF, Lanikova L, Dowey SN, He C, Huang X, Brodsky RA, Spivak JL, Prchal JT, Cheng L
المصدر: Stem cells (Dayton, Ohio) [Stem Cells] 2014 Jan; Vol. 32 (1), pp. 269-78.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Oxford University Press Country of Publication: England NLM ID: 9304532 Publication Model: Print Cited Medium: Internet ISSN: 1549-4918 (Electronic) Linking ISSN: 10665099 NLM ISO Abbreviation: Stem Cells Subsets: MEDLINE
أسماء مطبوعة: Publication: 2022- : Oxford : Oxford University Press
Original Publication: Dayton, OH : AlphaMed Press, c1993-
مواضيع طبية MeSH: Erythroblasts/*drug effects , Hematopoietic Stem Cells/*drug effects , Induced Pluripotent Stem Cells/*drug effects , Janus Kinase 2/*antagonists & inhibitors , Protein Kinase Inhibitors/*pharmacology, Cell Differentiation/drug effects ; Erythroblasts/enzymology ; Erythropoiesis/drug effects ; Hematopoiesis/drug effects ; Hematopoietic Stem Cells/cytology ; Hematopoietic Stem Cells/enzymology ; Humans ; Induced Pluripotent Stem Cells/cytology ; Induced Pluripotent Stem Cells/enzymology ; Janus Kinase 2/genetics
مستخلص: 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.
(© AlphaMed Press.)
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معلومات مُعتمدة: P01 CA108671 United States CA NCI NIH HHS; T32 HL007525 United States HL NHLBI NIH HHS; U01 HL107446 United States HL NHLBI NIH HHS; 1P01 CA108671-O1A2 United States CA NCI NIH HHS
فهرسة مساهمة: Keywords: Erythropoiesis; Hematopoietic malignancies; Hematopoietic progenitor cells; Induced pluripotent stem cells; Preclinical drug evaluation
المشرفين على المادة: 0 (Protein Kinase Inhibitors)
EC 2.7.10.2 (Janus Kinase 2)
تواريخ الأحداث: Date Created: 20131010 Date Completed: 20141106 Latest Revision: 20211021
رمز التحديث: 20221213
مُعرف محوري في PubMed: PMC4096297
DOI: 10.1002/stem.1545
PMID: 24105986
قاعدة البيانات: MEDLINE
الوصف
تدمد:1549-4918
DOI:10.1002/stem.1545