Abstract | BACKGROUND: METHODS: 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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Authors | Rui Zhao, George A Follows, Philip A Beer, Linda M Scott, Brian J P Huntly, Anthony R Green, Denis R Alexander |
Journal | The New England journal of medicine
(N Engl J Med)
Vol. 359
Issue 26
Pg. 2778-89
(Dec 25 2008)
ISSN: 1533-4406 [Electronic] United States |
PMID | 19109573
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | 2008 Massachusetts Medical Society |
Chemical References |
- Cation Transport Proteins
- SLC9A1 protein, human
- Sodium-Hydrogen Exchanger 1
- Sodium-Hydrogen Exchangers
- bcl-X Protein
- Protein-Tyrosine Kinases
- Fusion Proteins, bcr-abl
- Janus Kinase 2
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Topics |
- Apoptosis
- Cation Transport Proteins
(genetics)
- Cell Line, Tumor
- DNA Damage
(genetics)
- Deamination
- Fusion Proteins, bcr-abl
(genetics, physiology)
- Gene Transfer Techniques
- Genes, abl
(genetics)
- Humans
- Janus Kinase 2
(genetics)
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive
(blood, genetics)
- Leukocytes, Mononuclear
- Myeloproliferative Disorders
(blood, genetics)
- Polycythemia Vera
(blood, genetics)
- Protein-Tyrosine Kinases
(genetics, physiology)
- Signal Transduction
(genetics)
- Sodium-Hydrogen Exchanger 1
- Sodium-Hydrogen Exchangers
(genetics)
- bcl-X Protein
(genetics, physiology)
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