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Oncogene. 2017 Apr;36(15):2066-2073. doi: 10.1038/onc.2016.362. Epub 2016 Oct 3.

MYC selects against reduced BCL2A1/A1 protein expression during B cell lymphomagenesis.

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Division of Developmental Immunology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria.
Institute of Pharmacology and Toxicology, Department of Biomedical Sciences, University of Veterinary Medicine, Vienna, Austria.
Tyrolean Cancer Research Institute, Innsbruck, Austria.


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.

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