Peripheral T-cell lymphomas (PTCLs) constitute a heterogeneous and poorly understood pathological group of non-Hodgkin lymphomas associated with poor prognosis. Little is known on the genetics and mechanisms of this disease and better diagnostic tools, prognostic biomarkers and therapeutic targets are urgently needed in the clinic. Recently we have identified new genetic alterations in PTCL transformation by using a combination of whole exome sequencing of tumor-normal DNA pairs, RNAseq analysis and targeted deep sequencing of candidate genes. Our data identified highly recurrent mutations in the RHOA oncogene including a highly prevalent RHOA G17V allele present in almost 70% of angioimmunoblastic T- cell lymphomas (AITL) and almost 20% of PTCL not otherwise specified (PTCL NOS) samples. Our central hypothesis is that the RHOA G17V mutation acts as a negative regulator of RHOA signaling and as an oncogenic driver of PTCL. The goals of this research are to identify the mechanisms and pathways by which RHOA G17V contribute to T-cell transformation and to analyze the oncogenic effects of this mutation in the pathogenesis of AITL in vivo using a mouse model of RhoA G17V induced lymphoma.

Public Health Relevance

This project aims to analyze the mechanisms of T-cell transformation induced by the RHOA G17V mutation using a combination of biochemical, cellular and genetic approaches, genomic tools and animal models. Elucidation of the specific mechanisms mediating the oncogenic effects of RHOA G17V will provide important novel insight on the pathogenesis of angioimmunoblastic T-cell tumors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA197945-01
Application #
8946177
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Jhappan, Chamelli
Project Start
2015-07-01
Project End
2020-06-30
Budget Start
2015-07-01
Budget End
2016-06-30
Support Year
1
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Pathology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Abate, Francesco; da Silva-Almeida, Ana C; Zairis, Sakellarios et al. (2017) Activating mutations and translocations in the guanine exchange factor VAV1 in peripheral T-cell lymphomas. Proc Natl Acad Sci U S A 114:764-769
Cortés, José R; Palomero, Teresa (2016) The curious origins of angioimmunoblastic T-cell lymphoma. Curr Opin Hematol 23:434-43
da Silva Almeida, Ana Carolina; Abate, Francesco; Khiabanian, Hossein et al. (2015) The mutational landscape of cutaneous T cell lymphoma and Sézary syndrome. Nat Genet 47:1465-70