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Mutated JAK2 signal transduction in human induced pluripotent stem cell (iPSC)-derived megakaryocytes.

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  • معلومة اضافية
    • المصدر:
      Publisher: Informa Healthcare Country of Publication: England NLM ID: 9208117 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1369-1635 (Electronic) Linking ISSN: 09537104 NLM ISO Abbreviation: Platelets Subsets: MEDLINE
    • بيانات النشر:
      Publication: London : Informa Healthcare
      Original Publication: Edinburgh ; New York : Churchill Livingstone, c1990-
    • الموضوع:
      Induced Pluripotent Stem Cells* ; Janus Kinase 2*/genetics ; Janus Kinase 2*/metabolism ; Signal Transduction* ; Thrombocythemia, Essential*/genetics; Arsenic Trioxide/pharmacology ; Doxycycline ; Humans ; Interferon-alpha/pharmacology ; Megakaryocytes/metabolism ; Mutation ; Proto-Oncogene Proteins c-akt/metabolism ; STAT5 Transcription Factor/genetics ; STAT5 Transcription Factor/metabolism
    • نبذة مختصرة :
      Janus kinase 2 ( JAK2 ) gene mutations are the main drivers for polycythemia vera (PV) and essential thrombocythemia (ET). The mechanisms of single altered gene causing two different diseases are unclear. Additionally, novel treatments specifically targeting mutated JAK2 proteins are needed. In this study, the induced pluripotent stem cells (iPSCs) were virally transduced to express wild-type JAK2 (JAK2WT), JAK2 p.V617F (JAK2V617F) or JAK2 p.N542_E543del (JAK2exon12) under a doxycycline-inducible system. The modified iPSCs which were differentiated into megakaryocytes in the presence vs . absence of doxycycline were compared to ensure that the differences were solely from mutated JAK2 expressions. The JAK2V617-expressing iPSCs yielded significantly higher numbers of megakaryocytes consistent with the ET phenotype, while there was no enhancement by JAK2exon12 expression compatible with the pure erythrocytosis in humans. Capillary Western analyses revealed significantly greater JAK2 phosphorylation in iPSCs carrying JAK2V617F but not in JAK2WT and JAK2exon12 iPSCs. Activation of STAT3, STAT5 and AKT was increased by JAK2V617F, while they were decreased in JAK2exon12 iPSCs. Notably, interferon alpha and/or arsenic trioxide inhibited megakaryocytes proliferation and reduced JAK2, STAT3, STAT5 and AKT phosphorylation in mutant JAK2-expressing iPSCs compared with those without induction. In conclusion, JAK2V617F expression in iPSCs preferentially promoted megakaryocytes with a signaling profile distinctive from JAK2exon12 expression. Treatments with interferon alpha or arsenic trioxide preferentially suppressed the mutated over wild-type JAK2 signaling. This iPSC model is helpful in mechanistic studies and novel therapy screen for myeloproliferative neoplasm.
    • Contributed Indexing:
      Keywords: Interferon; iPSCs; megakaryocytes; myeloproliferative neoplasms; signal transduction
    • الرقم المعرف:
      0 (Interferon-alpha)
      0 (STAT5 Transcription Factor)
      EC 2.7.10.2 (JAK2 protein, human)
      EC 2.7.10.2 (Janus Kinase 2)
      EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
      N12000U13O (Doxycycline)
      S7V92P67HO (Arsenic Trioxide)
    • الموضوع:
      Date Created: 20211109 Date Completed: 20220530 Latest Revision: 20220601
    • الموضوع:
      20250114
    • الرقم المعرف:
      10.1080/09537104.2021.1981850
    • الرقم المعرف:
      34749590