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Background 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.
Source Information
From the Laboratory of Lymphocyte Signalling and Development, Babraham Institute (R.Z., D.R.A.), and the Cambridge Institute for Medical Research, Addenbrooke's Hospital (G.A.F., P.A.B., L.M.S., B.J.P.H., A.R.G.), University of Cambridge, Cambridge, United Kingdom.
Drs. Green and Alexander contributed equally to this article.
Address reprint requests to Dr. Zhao at the Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Cambridge CB2 4AT, United Kingdom, or at rui.zhao{at}bbsrc.ac.uk; or to Dr. Green at the Cambridge Institute for Medical Research, Hills Rd., Cambridge CB2 2XY, United Kingdom, or at arg1000{at}cam.ac.uk.
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