Characterization of the spectrum of trivalent VAV1‐mutation‐driven tumours using a gene‐edited mouse model

Abstract

Mutations in the VAV1 guanine nucleotide exchange factor 1 have been recently found in peripheral T cell lymphoma and nonsmall‐cell lung cancer (NSCLC). To understand their pathogenic potential, we generated a gene‐edited mouse model that expresses a VAV1 mutant protein that recapitulates the signalling alterations present in the VAV1 mutant subclass most frequently found in tumours. We could not detect any overt tumourigenic process in those mice. However, the concurrent elimination of the Trp53 tumour suppressor gene in them drives T cell lymphomagenesis. This process represents an exacerbation of the normal functions that wild‐type VAV1 plays in follicular helper T cells. We also found that, in combination with the Kras oncogene, the VAV1 mutant version favours progression of NSCLC. These data indicate that VAV1 mutations play critical, although highly cell‐type‐specific, roles in tumourigenesis. They also indicate that such functions are contingent on the mutational landscape of the tumours involved.

Role of Vav1, a hematopoietic signal transduction molecule, as an adaptor protein in health and disease

“…Using a GEMM approach, Fukumoto et al [108] demonstrated that the ectopic expression of Vav1 gain-of-function mutations, Vav1 (165-174del) and Vav1-STAP2, leads to the development of T cell lymphomagenesis only when tumor protein P53 (TP53), a tumor suppressor gene is deleted [108]. In a similar study, Robles-Valero et al [117] showed in a gene-edited mouse model that the trivalent functional subclass of Vav1 mutations plays critical roles in the development of AITL, yet it requires the elimination of the suppressor activity of TP53. It is possible that the requirement for loss of TP53 is related to issues such as overcoming the negative selection that is probably imposed on thymocytes expressing active versions of Vav1.…”

“…The contribution of wild-type Vav1 [114][115][116] or Vav1 mutants [108,117] to tumor development has been studied in vivo recently, using genetically engineered mouse models (GEMMs). Expression of wild-type Vav1 in specific organs, such as the lungs [114] or the pancreas [116], indicated that while expression of Vav1 only did not lead to tumor development, co-expression of Vav1 with mutant K-Ras (K-Ras G12D /Vav1 mouse) synergistically enhanced tumor development in these organs [114,116].…”

Unraveling the Oncogenic Potential of VAV1 in Human Cancer: Lessons from Mouse Models

“…The contribution of wild-type VAV1 [81][82][83] or VAV1 mutants [110,111] has recently been studied in vivo using GEMMs, as detailed below.…”

“…This pro-tumorigenic effect engages both the GEF-dependent and GEF-independent activities of VAV1 mutants [108]. In a gene-edited mouse model, Robles-Valero et al [111] showed that the trivalent functional subclass of VAV1 mutations plays a critical role in the development of AITL when the suppressor TP53 is inactive. The requirement for the loss of TP53 may be related to problems such as overcoming the negative selection likely imposed on thymocytes expressing the active version of VAV1 [111].…”

“…In a gene-edited mouse model, Robles-Valero et al [111] showed that the trivalent functional subclass of VAV1 mutations plays a critical role in the development of AITL when the suppressor TP53 is inactive. The requirement for the loss of TP53 may be related to problems such as overcoming the negative selection likely imposed on thymocytes expressing the active version of VAV1 [111]. Taken together, even severe mutations that deregulate and activate VAV1 function are insufficient to act alone as oncogenes and require additional molecular lesions.…”