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ArtikelInhibition of the Bcl-xL Deamidation Pathway in Myeloproliferative Disorders  
Oleh: Rui, Zhao ; Follows, George A. ; Beer, Philip A. ; Scott, Linda M.
Jenis: Article from Journal - ilmiah internasional
Dalam koleksi: The New England Journal of Medicine (keterangan: ada di Proquest) vol. 359 no. 26 (Dec. 2008), page 2778-2789.
Topik: Bcl-xL deamidation pathway; myeloproliferative disorders
Ketersediaan
  • Perpustakaan FK
    • Nomor Panggil: N08.K.2008.06
    • Non-tandon: 1 (dapat dipinjam: 0)
    • Tandon: tidak ada
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Isi artikelBackground : The myeloproliferative disorders are clonal disorders with frequent somatic gain-of-function alterations affecting tyrosine kinases. In these diseases, there is an increase in DNA damage and a risk of progression to acute leukemia. The molecular mechanisms in myeloproliferative disorders that prevent apoptosis induced by damaged DNA are obscure. Methods : We searched for abnormalities of the proapoptotic Bcl-xL deamidation pathway in primary cells from patients with chronic myeloid leukemia (CML) or polycythemia vera, myeloproliferative disorders associated with the BCR-ABL fusion kinase and the Janus tyrosine kinase 2 (JAK2) V617F mutation, respectively. Results : The Bcl-xL deamidation pathway was inhibited in myeloid cells, but not T cells, in patients with CML or polycythemia vera. DNA damage did not increase levels of the amiloride-sensitive sodium–hydrogen exchanger isoform 1 (NHE-1), intracellular pH, Bcl-xL deamidation, and apoptosis. Inhibition of the pathway was reversed by enforced alkalinization or overexpression of NHE-1, leading to a restoration of apoptosis. In patients with CML, the pathway was blocked in CD34+ progenitor cells and mature myeloid cells. Imatinib or JAK2 inhibitors reversed inhibition of the pathway in cells from patients with CML and polycythemia vera, respectively, but not in cells from a patient with resistance to imatinib because of a mutation in the BCR-ABL kinase domain. Conclusions : BCR-ABL and mutant JAK2 inhibit the Bcl-xL deamidation pathway and the apoptotic response to DNA damage in primary cells from patients with CML or polycythemia vera.
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