Inhibition of the Bcl-x(L) Deamidation Pathway in Myeloproliferative Disorders

Zhao, Rui, Follows, George A., Beer, Philip A., Scott, Linda M., Huntly, Brian J. P., Green, Anthony R. and Alexander, Denis R. (2008) Inhibition of the Bcl-x(L) Deamidation Pathway in Myeloproliferative Disorders. New England Journal of Medicine, 359 26: 2778-2789. doi:10.1056/NEJMoa0804953

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Author Zhao, Rui
Follows, George A.
Beer, Philip A.
Scott, Linda M.
Huntly, Brian J. P.
Green, Anthony R.
Alexander, Denis R.
Title Inhibition of the Bcl-x(L) Deamidation Pathway in Myeloproliferative Disorders
Journal name New England Journal of Medicine   Check publisher's open access policy
ISSN 0028-4793
1533-4406
Publication date 2008-12-25
Year available 2008
Sub-type Article (original research)
DOI 10.1056/NEJMoa0804953
Open Access Status File (Publisher version)
Volume 359
Issue 26
Start page 2778
End page 2789
Total pages 12
Place of publication Boston, MA, United States
Publisher Massachusetts Medical Society
Language eng
Formatted abstract
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.
Keyword Chronic Myeloid-Leukemia
X-L Deamidation
Chronic Myelogenous Leukemia
Tyrosine Kinase Jak2
Abl-Positive Cells
Polycythemia-Vera
Bcl-X
Dna-Damage
Essential Thrombocythemia
V617F Mutation
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Unknown

Document type: Journal Article
Sub-type: Article (original research)
Collection: UQ Diamantina Institute Publications
 
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