Inhibition of the Bcl-xL Deamidation Pathway in Myeloproliferative Disorders

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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-xL 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-xL 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-xL 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-xL deamidation pathway and the apoptotic response to DNA damage in primary cells from patients with CML or polycythemia vera.

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