MYD88 mutations, found in 39% of activated B cell type of diffuse large B cell lymphomas (ABC-DLBCL) and almost 100% of Waldenström’s macroglobulinemia (WM), have emerged as one of the most frequent mutations in mature B cell lymphoproliferative diseases. Three-quarters of all MYD88 mutations result in the single amino acid substitution, leucine 265 to proline (L265P). ABC-DLBCL and WM cells with the MYD88 L265P mutation also frequently carry CD79B mutations, mainly in its ITAM motif. Here, we show the cooperation between MYD88 and CD79B mutations for B cell survival and break of tolerance. MYD88 L265P mutation, but not CD79B ITAM mutation, drives mitogen independent B cell proliferation and NFκB activation, which is nevertheless negatively regulated by TNFAIP3/A20. The MYD88 L265P mutation alone reduces mature surface BCR expression by inhibiting maturation of CD79B protein without changing its transcription and translation. Co-expression of MYD88 and CD79B proteins in mature B cells results in the rescue of surface BCR expression, prolonged B cell survival in-vivo, break of tolerance to self-antigen, plasma cell differentiation and auto-antibody secretion. More drastic CD79B reduction was observed in B cells expressing constitutively active IKKβ mutation, indicating an IKK-dependent mechanism. The IKKβ mutant drives mitogen independent B cell proliferation in vitro, however these B cells fail to survive in vivo, consistent with the previous study that B cells that lack surface BCR fail to survive in vivo for more than 3-5 days. Our findings reveal that surface BCR expression is critical for the survival of B cells carrying lymphoma derived mutations for dysregulating B cell tolerance, providing an experimental explanation for the frequent accumulation of CD79B ITAM mutations in lymphomas carrying the MYD88 L265P mutation.