B-cell chronic lymphocytic leukemia (B-CLL) is a heterogeneous disease involving more than one molecular mechanism that leads to the transformation of CD5(+) B cells at either the pregerminal or post-germinal center stage of differentiation. It was previously demonstrated that ataxia telangiectasia mutated (ATM) gene mutations can occur in B-CLL and cause a defect in the p53 pathway. Here the role of ATM mutations in the pathogenesis of B-CLL is addressed. Of 50 B-CLL tumors with fully analyzed ATM and TP53, 16 had ATM mutations. Six of 50 B-CLLs showed mutations in TP53 and the remaining 28 tumors had wild-type ATM or TP53. No tumor had both ATM and TP53 mutations. Remarkably, all 16 ATM mutant B-CLLs showed the absence of somatic variable region heavy chain hypermutation indicating a pregerminal center cell origin and a common pathogenesis for these tumors. Furthermore, in 5 of the 16 B-CLLs, ATM mutation preceded the transformation stage of differentiation. At the cellular level, ATM mutant tumors exhibited a deficient ATM-dependent p53 response to gamma irradiation, failure to up-regulate TRAIL-R2, a downstream target that links irradiation-induced p53 response with apoptosis, and an inability to repair induced chromosome breaks. Mantle cell lymphoma (MCL) is also of pregerminal center origin and ATM mutations are frequent in this malignancy. It is concluded that ATM is likely to play an important role at the pregerminal center stage and a model is proposed where loss of ATM function during B-cell ontogeny drives B-CLL tumorigenesis in pregerminal B cells by a dual defect in p53 damage response and repair of chromosome breaks.