Journal
CANCER CELL
Volume 33, Issue 2, Pages 259-+Publisher
CELL PRESS
DOI: 10.1016/j.ccell.2018.01.001
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Funding
- National Cancer Institute [R01 CA197945-01]
- Leukemia & Lymphoma Society [TRP-6507-17, TRP-6163-12]
- Institut National Du Cancer (INCA) [2013-1-PL BIO-09, INCa-DGOS-INSERM 6043]
- equipe labellisee Ligue Nationale Contre le Cancer (LNCC)
- INCa (Institut National du Cancer, France) [INCa-DGOS-INSERM 6043]
- Leukemia and Lymphoma Society
- ITMO (Institut Multi Organismes Cancer, France)
- INCa
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Angioimmunoblastic T cell lymphoma (AITL) is an aggressive tumor derived from malignant transformation of T follicular helper (Tfh) cells. AITL is characterized by loss-of-function mutations in Ten-Eleven Translocation 2 (TET2) epigenetic tumor suppressor and a highly recurrent mutation (p.Gly17Val) in the RHOA small GTPase. Yet, the specific role of RHOA G17V in AITL remains unknown. Expression of Rhoa G17V in CD4(+) T cells induces Tfh cell specification; increased proliferation associated with inducible co-stimulator (ICOS) upregulation and increased phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase signaling. Moreover, RHOA G17V expression together with Tet2 loss resulted in development of AITL in mice. Importantly, Tet2(-/-) RHOA G17V tumor proliferation in vivo can be inhibited by ICOS/PI3K-specific blockade, supporting a driving role for ICOS signaling in Tfh cell transformation.
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