BIM mediates oncogene inactivation-induced apoptosis in multiple transgenic mouse models of acute lymphoblastic leukemia.
Oncogene inactivation in both clinical targeted therapies and conditional transgenic mouse cancer models can induce significant tumor regression associated with the robust induction of apoptosis. Here we report that in MYC-, RAS-, and BCR-ABL-induced acute lymphoblastic leukemia (ALL), apoptosis upon oncogene inactivation is mediated by the same pro-apoptotic protein, BIM. The induction of BIMin the MYC- and RAS-driven leukemia is mediated by the downregulation of miR-17-92. Overexpression of miR-17-92 blocked the induction of apoptosis upon oncogene inactivation in the MYC and RAS-driven but not in the BCR-ABL-driven ALL leukemia. Hence, our results provide novel insight into the mechanism of apoptosis upon oncogene inactivation and suggest that induction of BIM-mediated apoptosis may be an important therapeutic approach for ALL.
Division of Oncology, Department of Medicine and Pathology, Stanford University, Stanford, CA, United States of America.
Yulin
Y
Li
Division of Oncology, Department of Medicine and Pathology, Stanford University, Stanford, CA, United States of America.
Anja
A
Deutzmann
Division of Oncology, Department of Medicine and Pathology, Stanford University, Stanford, CA, United States of America.
Peter S
PS
Choi
Division of Oncology, Department of Medicine and Pathology, Stanford University, Stanford, CA, United States of America.
Alice C
AC
Fan
Division of Oncology, Department of Medicine and Pathology, Stanford University, Stanford, CA, United States of America.
Dean W
DW
Felsher
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D000072224:Bcl-2-Like Protein 11 / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004318:Doxycycline / Q000494:pharmacology; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics; D009857:Oncogenes / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference
D000072224:Bcl-2-Like Protein 11; C575895:MIRN17-92 microRNA, mouse; D035683:MicroRNAs; D016271:Proto-Oncogene Proteins c-myc; D016044:Fusion Proteins, bcr-abl; D016283:Proto-Oncogene Proteins p21(ras); D004318:Doxycycline
BIM; apoptosis; oncogene inactivation; targeted therapies