Inhibition of the Bcl-xL Deamidation Pathway in Myeloproliferative Disorders

DNA damage in normal cells triggers a newly discovered pathway that raises intracellular pH, which in turn deaminates and impairs the antiapoptotic Bcl-x L protein, thereby causing an increase in apoptosis. This pathway was found to be suppressed in mature myeloid cells and stem cells from patients with chronic myeloid leukemia and polycythemia vera. The Bcl-x L pathway was found to be suppressed in mature myeloid cells and stem cells from patients with chronic myeloid leukemia and polycythemia vera. Chronic myeloid leukemia (CML) and polycythemia vera are clonal myeloproliferative disorders that are associated with the activation of distinct tyrosine kinases, the BCR-ABL fusion kinase 1 and the Janus tyrosine kinase 2 (JAK2) mutation, 2 , 3 respectively. In both disorders, patients usually present with chronic disease, which is readily controlled. However, for reasons that are unclear, both diseases carry a risk of progression to a blastic phase resembling acute leukemia that resists further therapy. The cellular prosurvival protein Bcl-x L is up-regulated in patients with CML and polycythemia vera and is thought to inhibit apoptosis. 4 – 7 Moreover, BCR-ABL protein expression is associated . . .