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 Blood, 1 February 2008, Vol. 111, No. 3, pp. 1665-1676.
Prepublished online as a Blood First Edition Paper on November 21, 2007; DOI 10.1182/blood-2007-09-110601.

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NEOPLASIA

Lentiviral (HIV)-based RNA interference screen in human B-cell receptor regulatory networks reveals MCL1-induced oncogenic pathways

Antonio Ruiz-Vela1, Mohit Aggarwal1, Paloma de la Cueva1, Cezary Treda1, Beatriz Herreros1, Daniel Martín-Pérez1, Orlando Dominguez2, and Miguel A. Piris1

1 Lymphoma Group, Department of Molecular Pathology and 2 Genomics Unit, Biotechnology Program, Spanish National Cancer Centre, Madrid, Spain

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 β-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.


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