Inhibition of Bcl-x_L Deamidation Pathway in Myeloproliferation

Chronic myeloid leukemia (CML) and polycythemia vera (PV) are clonal diseases characterized by progressive accumulation of myeloid elements, occasional transformation to acute myeloid leukemia, activation of specific tyrosine kinases (BCR-ABL fusion kinase in CML and JAK2 mutation in PV), and upregulation of the antiapoptotic protein Bcl-x_L. Recently, the pathway for inactivation of Bcl-x_L has been elucidated: DNA damage increases activity of sodium-hydrogen exchanger (NHE-1), which leads to a rise in intracellular pH (alkalinization). In turn, increased pH promotes the removal of amide groups from Bcl-x_L, which prevents Bcl-x_L from inhibiting proapoptotic proteins, thus blocking apoptosis. Now investigators have examined this pathway in pa…