Inhibition of the Bcl-xL deamidation pathway in myeloproliferative disorders.

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.

• 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)
• 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

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)