Role and Mechanisms of VAV1 alterations in Peripheral T-cell Lymphomas

项目摘要/摘要 外周T细胞淋巴瘤(PTCL)是一种异质性且知之甚少的疾病 病理组的非霍奇金淋巴瘤预后不良。尽管有重大的 近年来发现PTCL的基因组驱动因素的进展，了解它们的 转化机制和确定治疗靶点仍然是 菲尔德。最近，我们在PTCL中发现了Vav1癌基因的新的遗传改变 RNAseq分析和候选基因的定向测序相结合。大多数Vav1 基因组改变是指影响C端结构域的融合和微小的基因内缺失 蛋白质。我们的中心假设是Vav1基因的改变导致了 Vav1下游的信号通路是PTCL的致癌驱动因素。我们的预赛 结果表明，复发的Vav1-myo1f融合的表达诱导了淋巴瘤 概述高危PTCL的组织学和分子病理学。这个项目的目标是 Vav1-MYO1F融合促进小鼠淋巴肿大的机制 并探索PTCL临床前模型中新出现的特定治疗漏洞。

Project Summary/Abstract Peripheral T-cell lymphomas (PTCLs) represent a heterogeneous and poorly understood pathological group of non-Hodgkin lymphomas associated with poor prognosis. Despite major progress in recent years in the identification of genomic drivers in PTCL, understanding their mechanisms of transformation and identifying therapeutic targets remain a high priority in the field. Recently we have identified novel genetic alterations in the VAV1 oncogene in PTCL using a combination of RNAseq analysis and targeted sequencing of candidate genes. Most VAV1 genomic alterations are fusions and small intragenic deletions affecting the C-terminal domain of the protein. Our central hypothesis is that the VAV1 alterations lead to increase activation of signaling pathways downstream of VAV1 and act as oncogenic drivers of PTCL. Our preliminary results demonstrate that expression of the recurrent Vav1-myo1f fusion induces lymphomas that recapitulate the histology and molecular pathology of high-risk PTCL. The goals of this project are to characterize the mechanisms by which VAV1-MYO1F fusion promotes lymphomagenesis in vivo and to explore emerging specific therapeutic vulnerabilities in PTCL preclinical models.