Differential Survival Requirements For Lck- And Cd3e-Dependent Signaling Defines Two Populations Of Atmko Thymic T Cell Lymphomas

Abstract The product of theataxia-telangiectasia mutated gene (ATM) is a serine-threonine kinase thatcommunicates between molecules that detect dangerous DNA double strand breaksand effector mechanisms that maintain genomic integrity. ATM deficiency in bothhumans and mice is associated with genomic instability and increased malignancies. ATMKO mice exclusively develop thymic T cell lymphomas that resemble thymically-derivedT-ALL that occur in human ATM-deficient ataxia telangiectasia patients. Flowcytometry identified two subsets of ATMKO T cell lymphomas based on surfaceexpression of CD3ɛ, TCRβ and pre-Tα:Cells that express surface CD3ɛ, TCRβ and pre-Tα(surface receptor high; sRhi) and cells that do not express detectable surface CD3ɛ, TCRβ orpre-Tα(sRlo). When assayed for CD25 and CD44 expression sRhi lymphomas resemble DN3or DN4 cells while sRlo lymphomas resemble more immature DN1 or DN2 cells. Pre-TCRsignaling in normal DN3 and DN4 thymocytes provides an essential survivalsignal that is proposed to be constitutive and ligand-independent. Therefore, weasked if surface sRhi and sRlo cells are dependent on pre-TCR signaling byincubating cells with either Lck inhibitor, CAS 213743-31-8, or CD3ɛshRNA to inhibit pre-TCR signaling. Both treatments significantly inhibitedsurvival of sRhi lymphomas, while survival of sRlo cells was largely unaffected. These results suggest that ATMKO T celllymphomas arise from cells transformed at different stages of DN development andthat sRhigh cells, like normal DN3 and DN4 thymocytes, retain apre-TCR-dependent survival requirement. These results also suggest that pre-TCRsignaling may be a useful target for clinical intervention in treatment ofhuman T-ALL that express a pre-TCR.