Abstract
Rearrangements of MYC or ABL proto-oncogenes lead to deregulated expression of key-regulators of cell cycle and cell survival, thereby constituting important drivers of blood cancer. Members of the BCL-2 family of apoptosis regulators contribute to oncogenic transformation downstream of these oncogenes, but the role of anti-apoptotic BCL2A1/A1 in transformation and drug resistance caused by deregulation of these oncogenes remains enigmatic. Here we analyzed the role of A1 in MYC as well as ABL kinase-driven blood cancer in mice, employing in vivo RNAi. We report that overexpression of either oncogene leads to a significant increase in A1 protein levels in otherwise A1-negative B cell progenitors, indicating a key role downstream of these oncogenes to secure survival during transformation. Knockdown of A1 by RNAi, however, did not impact on tumor latency in v-Abl-driven pre-B-ALL. In contrast, A1 knockdown in premalignant Eμ-MYC mice caused a significant reduction of transgenic pre-B cells without impacting on tumor latency as the emerging lymphomas escaped silencing of A1 expression. These findings identify A1 as a MYC target that can be induced prematurely during B cell development to aid expansion of otherwise cell-death-prone MYC transgenic pre-B cells. Hence, A1 should be considered as a putative drug target in MYC-driven blood cancer.
Highlights
The role of anti-apoptotic BCL-2 family members as disease promoters and mediators of drug resistance in human cancer is well established. This prompted the development of BCL2 inhibitors, some of them well advanced in clinical trials, with one of them recently approved for the treatment of refractory chronic lymphocytic leukemia (CLL).[1]
Despite the large degree of redundancy of individual BCL-2 family proteins upon overexpression, cell type and trigger-specific survival dependences have been noted. This led to the concept of ‘BCL-2-family addiction’ of human cancers, which means that tumor cells depend regularly on one particular BCL-2 family protein for cell survival, despite the fact that more such proteins are found expressed in a given cancer cell type.[2]
Upon transformation with the p185 or the p210 variant of the BCR-ABL oncogene, protein expression was strongly elevated (Figure 1a), a fact that correlated well with their gained growth factor independence. This suggests that oncogenic ABL-kinase signaling increases A1 protein levels, possibly to implement factorindependent cell survival, and that A1 may be a relevant player for tumorigenesis or drug responsiveness in BCR-ABL+ pre-B-ALL
Summary
The role of anti-apoptotic BCL-2 family members as disease promoters and mediators of drug resistance in human cancer is well established. This prompted the development of BCL2 inhibitors, some of them well advanced in clinical trials, with one of them recently approved for the treatment of refractory chronic lymphocytic leukemia (CLL).[1]. Recent studies in human cancer cells and cell lines, as well as different animal models of blood cancer, including those for BCRABL-driven pre-B-ALL or MYC-driven B cell lymphomas, have assigned critical survival roles to anti-apoptotic MCL-1 with sometimes auxiliary roles for other survival factors, mainly BCL-X, but quite often dispensable roles for BCL-2 itself.[4,5]
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