Roles of Bim in Apoptosis of Normal and Bcr-Abl-Expressing Hematopoietic Progenitors

Abstract

Bcr-Abl kinase is known to reverse apoptosis of cytokine-dependent cells due to cytokine deprivation, although it has been controversial whether chronic myeloid leukemia (CML) progenitors have the potential to survive under conditions in which there are limited amounts of cytokines. Here we demonstrate that early hematopoietic progenitors (Sca-1 ؉ c-Kit ؉ Lin ؊ ) isolated from normal mice rapidly undergo apoptosis in the absence of cytokines. In these cells, the expression of Bim, a proapoptotic relative of Bcl-2 which plays a key role in the cytokine-mediated survival system, is induced. In contrast, those cells isolated from our previously established CML model mice resist apoptosis in cytokine-free medium without the induction of Bim expression, and these effects are reversed by the Abl-specific kinase inhibitor imatinib mesylate. In addition, the expression levels of Bim are uniformly low in cell lines established from patients in the blast crisis phase of CML, and imatinib induced Bim in these cells. Moreover, small interfering RNA that reduces the expression level of Bim effectively rescues CML cells from apoptosis caused by imatinib. These findings suggest that Bim plays an important role in the apoptosis of early hematopoietic progenitors and that Bcr-Abl supports cell survival in part through downregulation of this cell death activator.

BCR-ABL mutants spread resistance to non-mutated cells through a paracrine mechanism

“…13 Reduction of MCL1, BCL2 and BCL-xL has been observed in some studies but not in others. [31][32][33][34] Our data confirm the essential role of Bim, and also indicate a possible role for MCL1, BCL-xL, Bad and Bax. We observed that apoptosis of resistant cells, induced through JAK2 blocking, was characterized by overexpression of Bim, while MEK1/2 blocking had little effect.…”

The BCL-2 protein family, BH3-mimetics and cancer therapy

“…150,151 Furthermore, BMF as well as BIM are critical for the killing of non-transformed lymphoid cells as well as certain lymphoma cells by inhibitors of histone deacetylases. 110,135 BIM (with BAD and BMF also contributing) is critical for the killing of tumour cells that are dependent on oncogenic kinases by therapeutic agents that block their activity, such as inhibitors of MEK (acting downstream of mutant B-RAF in melanoma or colon carcinoma), 152 EGFR (lung cancer), [153][154][155] BCR-ABL (CML) 156,157 and VEGFR signalling (tumour angiogenesis). 158 Notably, a gene polymorphism that impairs the expression of BIM was found to explain the de novo resistance of BCR-ABL-driven CML to Gleevec and mutant EGFR-driven lung cancer to Iressa/ Tarceva in East Asian populations.…”

Life in the balance: how BH3-only proteins induce apoptosis

“…Thus, bortezomib kills melanoma cells but, surprisingly, not normal melanocytes, and acts in part by inducing Noxa expression in a p53-independent fashion [68,69]. Furthermore, the apoptosis of chronic myeloid leukemia cells elicited by the kinase inhibitor Gleevec (imatinib mesylate) relies in part on Bim [70].…”