MYC protein dysregulation is driven by BCR‐PI3K signalling in diffuse large B‐cell lymphoma

• Published in: Histopathology 2017-11, Vol.71 (5), p.778-785
• Main Authors: Wang, Wei‐Ge, Liu, Ze‐Bing, Jiang, Xiang‐Nan, Lee, Jimmy, Zhou, Xiao‐Yan, Li, Xiao‐Qiu
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; Adult; Aged; Aged, 80 and over; AKT protein; B-cell lymphoma; B-cell receptor; Dephosphorylation; diffuse large B‐cell lymphoma; Down-regulation; Female; Humans; Kinases; Lymphocytes B; Lymphoma; Lymphoma, Large B-Cell, Diffuse - metabolism; Lymphoma, Large B-Cell, Diffuse - pathology; Male; Middle Aged; MYC; Myc protein; Neoplasia; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation; Proto-Oncogene Proteins c-bcr - metabolism; Proto-Oncogene Proteins c-myc - metabolism; Receptors, Antigen, B-Cell - metabolism; Retrospective Studies; Signal transduction; Signal Transduction - physiology; Syk protein; Tumors; Young Adult
• ISSN: 0309-0167; 1365-2559
• DOI: 10.1111/his.13287

Aims MYC overexpression is a common feature of diffuse large B‐cell lymphoma (DLBCL) and is associated with poor prognosis in patients with this neoplasm. We aimed to investigate the underlying mechanisms of MYC dysregulation, as they have not been fully determined. Methods and results We immunohistochemically evaluated the correlation between B‐cell receptor (BCR)–phosphoinositide 3‐kinase (PI3K) pathway activity and MYC level in 108 cases of de‐novo DLBCL, 25 of which featured loss of BCR, and investigated the effects of BCR–PI3K signalling on MYC level and phosphorylation in DLBCL cell lines. The expression levels of phospho‐SYK and phospho‐AKT correlated with MYC expression in BCR‐positive DLBCL. MYC expression was significantly lower in BCR‐negative tumour tissues than in BCR‐positive tumour tissues. Upon BCR stimulation, the BCR‐positive cell lines showed active BCR–PI3K signalling and decreased MYC phosphorylation at T58, leading to an increased overall level of MYC. Conversely, inhibition of BCR–PI3K signalling increased MYC phosphorylation and thus resulted in a decreased overall level of MYC. No effects were observed in the BCR‐negative cell lines. Conclusions Overexpression of MYC in DLBCL can be driven by the BCR–PI3K signalling pathway via dephosphorylation at T58, and BCR inhibitors may exert their functions by down‐regulation of MYC.