期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 115, 期 7, 页码 E1511-E1519出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1716452115
关键词
T-ALL; Capicua; NOTCH activation; T cell development; MYC; transcriptional program
资金
- NIH/National Institute of Neurological Disorders and Stroke (NINDS) [R01 N5027699, R37 N5027699]
- Cancer Prevention and Research Institute of Texas [RP160283, RP140001]
- NIH/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [R01 DK092883]
- NIH/National Cancer Institute (NCI) [R01 CA183252]
- NIH/NINDS [F32 N5083091]
- Canadian Institutes of Health Research [201210MFE-290072-173743]
- Parkinson's Foundation [PF-JFA-1762]
- NIH/Intellectual and Developmental Disabilities Research Center (IDDRC) from the Eunice Kennedy Shriver National Institute of Child Health and Human Development [U54HD083092]
- Genomic and RNA Profiling Core at Baylor College of Medicine
- NIH/National Center for Research Resources (NCRR) [S10RR024574]
- NIH/National Institute of Allergy and Infectious Diseases (NIAID) [AI036211]
- NIH/NCI Grant [P30CA125123]
- EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT [U54HD083092] Funding Source: NIH RePORTER
- NATIONAL CANCER INSTITUTE [R01CA183252, P30CA125123] Funding Source: NIH RePORTER
- NATIONAL CENTER FOR RESEARCH RESOURCES [S10RR024574] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [P30AI036211] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK092883] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS027699, R37NS027699, F32NS083091] Funding Source: NIH RePORTER
Capicua (CIC) regulates a transcriptional network downstream of the RAS/MAPK signaling cascade. In Drosophila, CIC is important for many developmental processes, including embryonic patterning and specification of wing veins. In humans, CIC has been implicated in neurological diseases, including spinocerebellar ataxia type 1 (SCA1) and a neurodevelopmental syndrome. Additionally, we and others have reported mutations in CIC in several cancers. However, whether CIC is a tumor suppressor remains to be formally tested. In this study, we found that deletion of Cic in adult mice causes T cell acute lymphoblastic leukemia/lymphoma (T-ALL). Using hematopoietic-specific deletion and bone marrow transplantation studies, we show that loss of Cic from hematopoietic cells is sufficient to drive T-ALL. Cic-null tumors show up-regulation of the KRAS pathway as well as activation of the NOTCH1 and MYC transcriptional programs. In sum, we demonstrate that loss of CIC causes T-ALL, establishing it as a tumor suppressor for lymphoid malignancies. Moreover, we show that mouse models lacking CIC in the hematopoietic system are robust models for studying the role of RAS signaling as well as NOTCH1 and MYC transcriptional programs in T-ALL.
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