Details

Autor(en) / Beteiligte

• Amarante-Mendes, G P
• McGahon, A J
• Nishioka, W K
• Afar, DEH
• Witte, ON
• Green, DR

Titel

Bcl-2-independent Bcr - Abl-mediated resistance to apoptosis: Protection is correlated with up regulation of Bcl-x sub(L)

Ist Teil von

• Oncogene, 1998-03, Vol.16 (11), p.1383-1390

Erscheinungsjahr

1998

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• Bcr - Abl is the molecule responsible for both the transformation phenotype and the resistance to chemotherapeutic drugs found in chronic myelogenous leukemia (CML) cells. Wild-type HL-60, a transformed pro-myelocytic cell line, is very susceptible to apoptosis-inducing agents. We show here that expression of Bcr - Abl in HL-60 cells rendered them extremely resistant to apoptosis induced by a wide variety of agents. The antiapoptotic effect of Bcr - Abl was found to be independent of the phase of the cell cycle. Treatment with antisense oligonucleotides directed to bcr decreased the expression of the ectopic bcr - abl and restored susceptibility to apoptosis. Double mutations affecting the autophosphorylation site and the phosphotyrosine-binding motif (FLVRES) have been previously shown to impair the transforming activity of Bcr - Abl in fibroblasts and hematopoietic cells, however HL-60 cells expressing this double mutant molecule exhibited the same level of resistance to apoptosis as those expressing the wild-type Bcr - Abl. Interestingly, wild type and mutant Bcr - Abl induced in HL-60 cells a dramatic down regulation of Bcl-2 and increased the levels of Bcl-x sub(L). The level of Bax did not change in response to the presence of Bcr - Abl. Antisense oligonucleotides targeted to bcl-x down-regulated the expression of Bcl-x sub(L) and increased the susceptibility of HL-60.Bcr - Abl cells to staurosporine. Importantly, HL-60 cells overexpressing Bcl-x sub(L) showed higher expression of Bcl-x sub(L) but lower resistance to apoptosis when compared to HL-60.Bcr - Abl cells. The results described here show that Bcr - Abl is a powerful mammalian anti-apoptotic molecule and can act independently of Bcl-2. Bcl-x sub(L), however, seems to participate in part in Bcr - Abl-mediated resistance to apoptosis in HL-60 cells.