MYC selects against reduced BCL2A1/A1 protein expression during B cell lymphomagenesis.
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.
Division of Developmental Immunology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria.
M
M
Sochalska
Division of Developmental Immunology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria.
F
F
Schuler
Division of Developmental Immunology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria.
J G
JG
Weiss
Institute of Pharmacology and Toxicology, Department of Biomedical Sciences, University of Veterinary Medicine, Vienna, Austria.
M
M
Prchal-Murphy
Institute of Pharmacology and Toxicology, Department of Biomedical Sciences, University of Veterinary Medicine, Vienna, Austria.
V
V
Sexl
Division of Developmental Immunology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria.|Tyrolean Cancer Research Institute, Innsbruck, Austria.
A
A
Villunger
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D016393:Lymphoma, B-Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D015778:Minor Histocompatibility Antigens / Q000096:biosynthesis / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics*; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis / Q000235:genetics*
C096816:BCL2-related protein A1; D015778:Minor Histocompatibility Antigens; C489428:Myc protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc
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