Journal
NEW ENGLAND JOURNAL OF MEDICINE
Volume 359, Issue 26, Pages 2778-2789Publisher
MASSACHUSETTS MEDICAL SOC
DOI: 10.1056/NEJMoa0804953
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Funding
- Association for International Cancer Research
- Biotechnology and Biological Sciences Research Council
- U.K. Leukaemia Research Fund
- Wellcome Trust
- U.K. Medical Research Council
- Cancer Research UK
- National Institute for Health Research Cambridge Biomedical Research Center
- U.S. Leukemia and Lymphoma Society
- MRC [G116/187] Funding Source: UKRI
- Cancer Research UK [8961] Funding Source: researchfish
- Medical Research Council [G0300723B, G116/187] Funding Source: researchfish
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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-x(L) 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-x(L) 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-x(L) 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-x(L) deamidation pathway and the apoptotic response to DNA damage in primary cells from patients with CML or polycythemia vera.
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