The protooncogene Vav1 regulates murine leukemia virus-induced T-cell leukemogenesis

Abstract

Vav1 is expressed exclusively in hematopoietic cells and is required for T cell development and activation. Vav1-deficient mice show thymic hypocellularity due to a partial block during thymocyte development at the DN3 stage and between the double positive (DP) and single positive (SP) transition. Vav1 has been shown to play a significant role in several non-hematopoietic tumors but its role in leukemogenesis is unknown. To address this question, we investigated the role of Vav1 in retrovirus-induced T cell leukemogenesis. Infection of Vav1-deficient mice with the Moloney strain of murine leukemia virus (M-MuLV) significantly affected tumor phenotype without modulating tumor incidence or latency. M-MuLV-infected Vav1-deficient mice showed reduced splenomegaly, higher hematocrit levels and hypertrophic thymi. Notably, Vav1-deficient mice with M-MuLV leukemias presented with markedly lower TCRβ/CD3 levels, indicating that transformation occurred at an earlier stage of T cell development than in WT mice. Thus, impaired T cell development modulates the outcome of retrovirus-induced T cell leukemias, demonstrating a link between T cell development and T cell leukemogenesis.

Identification of Anti-tumor Cells Carrying Natural Killer (NK) Cell Antigens in Patients With Hematological Cancers

“…Target cell availability is probably maximal for NK cells in blood borne cancers, hence, we believe that these diseases will show the highest CD45RARO NK cell numbers; although these cells are unable to control the disease. Leukemogenesis in mouse is enhanced when the host immune system is impaired ( Garaude et al, 2008 , Kaminski et al, 2012 ) and more hematological cancer patients present severe NK cell dysfunctions ( Baier et al, 2013 ). Others and we have shown the requirement of fully functional NK cells to eradicate blood-borne tumors in several mouse models ( Karre et al, 1986 , Van Den Broek et al, 1995 , Pardo et al, 2002 , Aguilo et al, 2009 , Charni et al, 2009 , Charni et al, 2010 , Ramírez-Comet et al, 2014 ).…”