The role of RHOA G17V mutation in peripheral t-cell lymphomas

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 DESCRIPTION (provided by applicant): 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.