The SRC family kinase LYN redirects B cell receptor signaling in human SLP65-deficient B cell lymphoma cells

Abstract

SLP65 represents a critical component in (pre-) B cell receptor signal transduction but is compromised in a subset of pre-B cell-derived acute lymphoblastic leukemia. Based on these findings, we investigated (i.) whether SLP65-deficiency also occurs in mature B cell-derived lymphoma and (ii.) whether SLP65-deficient B cell lymphoma cells use an alternative B cell receptor signaling pathway in the absence of SLP65. Indeed, expression of SLP65 protein was also missing in a fraction of B cell lymphoma cases. While SLP65 is essential for B cell receptor-induced Ca 2 þ mobilization in normal B cells, B cell receptor engagement in SLP65-deficient as compared to SLP65-reconstituted B cell lymphoma cells resulted in an accelerated yet shortlived Ca 2 þ -signal. B cell receptor engagement of SLP65-deficient lymphoma cells involves SRC kinase activation, which is critical for B cell receptor-dependent Ca 2 þ -mobilisation in the absence but not in the presence of SLP65. As shown by RNA interference, the SRC kinase LYN is required for B cell receptor-induced Ca 2 þ release in SLP65-deficient B cell lymphoma cells but dispensable after SLP65-reconstitution. B cell receptor engagement in SLP65-deficient B cell lymphoma cells also resulted in tyrosine-phosphorylation of the proliferation-and survival-related MAPK1 and STAT5 molecules, which was sensitive to silencing of the SRC kinase LYN. Inhibition of SRC kinase activity resulted in growth arrest and cell death specifically in SLP65-deficient lymphoma cells. These findings indicate that LYN can short-circuit conventional B cell receptor signaling in SLP65-deficient B cell lymphoma cells and thereby promote activation of survival and proliferationrelated molecules.

Tyrosine kinase inhibition in diffuse large B-cell lymphoma: molecular basis for antitumor activity and drug resistance of dasatinib

“…These results suggest that the sequence of events in the lymphoma cells might be different from those in normal B cells. In support of this speculation, Sprangers et al 35 have found several human lymphoma cell lines that carry mutations in the BLNK gene including deletions, 3 0 truncations, mutations in splice sites and small deletions in tyrosine residue codons. Moreover, BCR signaling can be transmitted by the direct interaction between Lyn and PLCg1, causing calcium mobilization in the absence of BLNK.…”

Oncogenic association of the Cbp/PAG adaptor protein with the Lyn tyrosine kinase in human B-NHL rafts

“…39 Finally, in case of SLP-65 (BLNK) linker protein deficiency, a direct oncogenic activity was also demonstrated for the Lyn kinase. 40 Despite its oncogenic and regulatory properties, PAG appears redundant in lymphocyte physiology because mice with a disrupted Cbp/PAG gene exhibit normal lymphocyte activation and maturation. 41,42 PAG may therefore constitute an adaptor selectively capable of increasing the oncogenic potential of Lyn in B-NHL cells.…”

Runx1 is essential at two stages of early murine B-cell development

“…37 It is well established that Lyn-SFK are important mediators of IL7 and pre-BCR stimulation, but the exact mechanism is unknown. 38 Lyn-SFKs have been linked to Stat5 activation, 39 and IL7-STAT5 signaling pathways have been shown to be critical for repressing Igl-k rearrangements at the pro-B stage, 40,41 which could account for relatively high Igl-k rearrangements observed in the Runx1-deficient pro-/pre-B cells. Furthermore, the critical role of Lyn-SFK in pre-BCR signaling has also been demonstrated in mice with either a triple knockout (Blk, Lyn, Fyn) or that are transgenic for a constitutively active form of Blk.…”