The myeloid differentiation primary response gene 88 (MYD88) has been sequenced for mutations in a number of lymphoproliferative diseases. First discovered to be an oncogene in activated B-cell like diffuse large B-cell lymphoma (ABC-DLBCL), it was shown that 39% of ABC-DLBCL patient biopsies and cell lines carry a somatic mutation in MYD88. Surprisingly, 29% of those mutations result in a single L265P amino acid substitution. Subsequent studies up to date identified the same mutation in other diseases such as chronic lymphocytic leukaemia (CLL), Waldenström’s macroglobulinemia, mucosa-associated lymphoid tissue (MALT) lymphoma and marginal zone lymphoma (MZL). However the effects of this MYD88 mutation alone in B-cells is unknown. Here we show, by using a retroviral gene delivery system, when introduced into antigen activated mature B-cells, single MYD88 L265P mutation promotes a short burst of mitogen independent B-cell proliferation in-vitro and T-cell independent proliferation in-vivo. The short-lived nature of this proliferation could be attributed to a potent feedback of shutting down NFκB activity through TNFAIP3 and the activation of the mitochondrial apoptosis pathway. Combining MYD88 mutation with loss-of-function TNFAIP3 mutation or BCL2 over-expression resulted in rescue of NFκB shutdown and drastic increase in B-cell number through enhanced proliferation or survival respectively. Our results demonstrated that MYD88 mutation alone only promoted short-lived B-cell proliferation and that cooperation with other genetic lesions is required for lymphomagenesis.