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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.

Author information

1
Division of Developmental Immunology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria.
2
Institute of Pharmacology and Toxicology, Department of Biomedical Sciences, University of Veterinary Medicine, Vienna, Austria.
3
Tyrolean Cancer Research Institute, Innsbruck, Austria.

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.

PMID:
27694901
PMCID:
PMC5395700
DOI:
10.1038/onc.2016.362
[Indexed for MEDLINE]
Free PMC Article

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