Genome-wide RNAi screen identifies suppressors of BCR-ABL-induced leukemia
Arvindhan Nagarajan1, Matteo Forloni1, Amy Virbasius2, Julie Zhu2, Michael R. Green2, and Narendra Wajapeyee1
1Department of Pathology, Yale School of Medicine, New Haven, CT and 2Howard Hughes Medical Institute and Programs in Gene Function and Expression and Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA
ABSTRACT
Certain oncogenes that promote solid tumors, such as RAS and BRAF, induce senescence when expressed in primary cells. Oncogene-induced senescence plays an important role in suppressing tumorigenesis by preventing proliferation of cells at risk for neoplastic transformation. Thus, in many instances, genes involved in oncogene-induced senescence, such as TP53 and RB1, are also tumor suppressors. BCR-ABL is an oncogenic kinase derived from the translocation between chromosomes 9 and 22 that can transform myeloid progenitor cells and drives the development of the vast majority of chronic myeloid leukemia (CML) cases and 20%–30% of adult acute lymphoblastic leukemia (ALL) cases. We have recently found that BCR-ABL, as well as two other leukemogenic fusion-proteins, CBFB-MYH11 and RUNX1-ETO, can, likeRASand BRAF, induce senescence in primary human fibroblasts and hematopoietic progenitors. Our results imply that the development of BCR-ABL+ leukemias involves genetic and/or epigenetic alterations that inactivate one or more senescence-promoting genes. Consistent with this hypothesis, inactivation of genes known to promote senescence, such as TP53 and CDKN2A (p16INK4α/p14ARF), can cooperate with BCR-ABL in mouse models of CML, and CDKN2A deletions are frequently found in patients with BCR-ABL+ ALL. Significantly, these same genetic alterations can also confer resistance to imatinib, an inhibitor of BCR-ABL kinase activity that is the first-line treatment for CML. Thus, delineating the genes and regulatory pathways by which BCR-ABL induces senescence in primary cells will help identify genetic alterations that cooperate with BCR-ABL to promote leukemogenesis and are responsible for the emergence of imatinib resistance.
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