SELECTIVE REGULATION OF BCL-X-L BY A JAK KINASE-DEPENDENT PATHWAY IS BYPASSED IN MURINE HEMATOPOIETIC MALIGNANCIES

Bcl-2 family proteins are key regulators of apoptosis and function as cell death antagonists (e.g., Bcl-2, Bcl-X-L, and Mcl-1) or agonists ( e.g., Bar, Bad, and Bak). Here we report that among the Bcl-2 family o f proteins tested (Bcl-2, Bcl-X-L, Mcl-1, Bar, Bad, and Bak), Bcl-X-L was unique in that its protein levels were tightly regulated by hemopo ietins in both immortal and primary myeloid progenitors. Investigating signaling pathways utilized by cytokine receptors established that th e regulation of Bcl-X-L protein levels is mediated by the Jak kinase p athway and is independent of other signaling effecters including STATs , PI-3' kinase, and Ras. Moreover, we provide the first direct evidenc e that Bcl-X is altered in cancer, because bcl-X expression was activa ted selectively by retroviral insertions in murine myeloid and T-cell hemopoietic malignancies. Tumors harboring bcl-X insertions had altere d bcl-X RNAs, expressed elevated levels of Bcl-X, protein, and lacked the requirements for cytokines normally essential for cell survival. F inally, overexpression of Bcl-X-L effectively protected IL-3-dependent myeloid cells from apoptosis following removal of trophic factors. Th erefore, Bcl-X-L functions as a key cytokine regulated anti-apoptotic protein in myelopoiesis and contributes to leukemia cell survival.