Genome-wide RNA-mediated interference screen identifies miR-19 targets in Notch-induced T-cell acute lymphoblastic leukaemia.
MicroRNAs (miRNAs) have emerged as novel cancer genes. In particular, the miR-17-92 cluster, containing six individual miRNAs, is highly expressed in haematopoietic cancers and promotes lymphomagenesis in vivo. Clinical use of these findings hinges on isolating the oncogenic activity within the 17-92 cluster and defining its relevant target genes. Here we show that miR-19 is sufficient to promote leukaemogenesis in Notch1-induced T-cell acute lymphoblastic leukaemia (T-ALL) in vivo. In concord with the pathogenic importance of this interaction in T-ALL, we report a novel translocation that targets the 17-92 cluster and coincides with a second rearrangement that activates Notch1. To identify the miR-19 targets responsible for its oncogenic action, we conducted a large-scale short hairpin RNA screen for genes whose knockdown can phenocopy miR-19. Strikingly, the results of this screen were enriched for miR-19 target genes, and include Bim (Bcl2L11), AMP-activated kinase (Prkaa1) and the phosphatases Pten and PP2A (Ppp2r5e). Hence, an unbiased, functional genomics approach reveals a coordinate clampdown on several regulators of phosphatidylinositol-3-OH kinase-related survival signals by the leukaemogenic miR-19.
Mavrakis
Konstantinos J
KJ
Cancer Biology & Genetics Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA.
Wolfe
Andrew L
AL
Oricchio
Elisa
E
Palomero
Teresa
T
de Keersmaecker
Kim
K
McJunkin
Katherine
K
Zuber
Johannes
J
James
Taneisha
T
Khan
Aly A
AA
Leslie
Christina S
CS
Parker
Joel S
JS
Paddison
Patrick J
PJ
Tam
Wayne
W
Ferrando
Adolfo
A
Wendel
Hans-Guido
HG
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic; D055785:Gene Knockdown Techniques; D015329:Gene Rearrangement, T-Lymphocyte; D055106:Genome-Wide Association Study; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D009857:Oncogenes; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference; D051881:Receptor, Notch1 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D013997:Time Factors; D014161:Transduction, Genetic; D014178:Translocation, Genetic
D035683:MicroRNAs; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; D019869:Phosphatidylinositol 3-Kinases