Inhibition of the Bcl-xL deamidation pathway in myeloproliferative disorders.
N Engl J Med
; 359(26): 2778-89, 2008 Dec 25.
Article
em En
| MEDLINE
| ID: mdl-19109573
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Policitemia Vera
/
Dano ao DNA
/
Leucemia Mielogênica Crônica BCR-ABL Positiva
/
Proteína bcl-X
Limite:
Humans
Idioma:
En
Revista:
N Engl J Med
Ano de publicação:
2008
Tipo de documento:
Article
País de afiliação:
Reino Unido