Lentiviral (HIV)-based RNA interference screen in human B-cell receptor regulatory networks reveals MCL1-induced oncogenic pathways.
Aberrant inhibition of B-cell receptor (BCR)-induced programmed cell death pathways is frequently associated with the development of human auto-reactive B-cell lymphomas. Here, we integrated loss-of-function, genomic, and bioinformatics approaches for the identification of oncogenic mechanisms linked to the inhibition of BCR-induced clonal deletion pathways in human B-cell lymphomas. Lentiviral (HIV)-based RNA interference screen identified MCL1 as a key survival molecule linked to BCR signaling. Loss of MCL1 by RNA interference rendered human B-cell lymphomas sensitive to BCR-induced programmed cell death. Conversely, MCL1 overexpression blocked programmed cell death on BCR stimulation. To get insight into the mechanisms of MCL1-induced survival and transformation, we screened 41 000 human genes in a genome-wide gene expression profile analysis of MCL1-overexpressing B-cell lymphomas. Bioinformatic gene network reconstruction illustrated reprogramming of relevant oncoproteins within beta-catenin-T-cell factor signaling pathways induced by enforced MCL1 expression. Overall, our findings not only illustrate MCL1 as an aberrantly expressed reprogramming oncoprotein in follicular lymphomas but also highlight MCL1 as key therapeutic target.
Ruiz-Vela
Antonio
A
Lymphoma Group, Department of Molecular Pathology, Biotechnology Program, Spanish National Cancer Centre, Madrid, Spain. antonio.ruizvela@universia.es
Aggarwal
Mohit
M
de la Cueva
Paloma
P
Treda
Cezary
C
Herreros
Beatriz
B
Martín-Pérez
Daniel
D
Dominguez
Orlando
O
Piris
Miguel A
MA
D045744:Cell Line, Tumor; D002470:Cell Survival; D030541:Databases, Genetic; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D015894:Genome, Human / Q000235:genetics; D006678:HIV / Q000235:genetics*; D006801:Humans; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D011947:Receptors, Antigen, B-Cell / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction
D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011947:Receptors, Antigen, B-Cell