Concomitant high expression of Toll-like receptor (TLR) and B-cell receptor (BCR) signalling molecules has clinical implications in mantle cell lymphoma.
Mantle cell lymphoma (MCL) is an aggressive disease with frequent relapse. Targeted therapies against B-cell receptor (BCR) molecules have demonstrated improved outcomes in relapsed cases. However, clinical responses are slow and selective, with failure to attain complete remission in a significant subset of patients. Complex interaction of BCR signal transduction with toll-like receptor (TLR) and other pathways in MCL remains unknown, thus averting progress in development of targeted therapies. We have performed detailed digital quantification of BCR/TLR signalling molecules and their effector pathways in a cohort (n = 81) of MCL patients and correlated these data with overall survival. Hierarchical clustering model based on BCR/TLR genes revealed two distinct (BCRhighand BCRlow) subsets of patients (n = 32; 40%) with significant differences in expression (>1.5-fold change; p < 0.05). Higher levels of BTK/SYK/BLNK/CARD11/PLCG signalosome and lower expression of MALT1/BCL10 genes suggested tonic pattern of BCR activation. Amplified expression of TLR6/TLR7/TLR9 was noted in concert with hyper-responsiveness of BCR machinery. MYD88, a key TLR adaptor molecule, was not upregulated in any of these clusters, which may suggest a 'cross-talk' between BCR and TLR pathways. In sync with BCR/TLR signalling, we recorded significantly enhanced expression of genes associated with NF-kB pathway in BCRhighsubset of MCL patients. On univariate analysis, the BCRhighpatients showed a trend towards inferior clinical response to a standardized treatment protocol, compared with the BCRlowgroup (log rank, p = 0.043). In conclusion, we have identified hyperactive BCR/TLR signalling pathways and their effector downstream targets in a subset of MCL patients and associated it with poor clinical outcomes. Our study provides quantitative evidence at RNA expression level of possible concomitant collaboration between TLR and BCR signalling molecules in MCL. These data will provide further insights for future functional studies and, hence, development of targeted therapies for MCL patients. Copyright © 2015 John Wiley & Sons, Ltd.
Division of Hematology and Transfusion Medicine, Department of Pathology and Laboratory Medicine, University of Calgary/Calgary Laboratory Services (CLS), Calgary, Alberta, Canada.
Ariz
A
Akhter
Division of Hematology and Hematologic Malignancies, Tom Baker Cancer Center, University of Calgary, Calgary, Alberta, Canada.
Lesley
L
Street
Department of Biostatistics, Cross Cancer Institute, University of Alberta, Edmonton, Alberta, Canada.
Sunita
S
Ghosh
Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, Ontario, Canada.
Bruce F
BF
Burns
Department of Pathology and Laboratory Medicine, Prince Sultan Military Medical City, Riyadh, Saudi Arabia.
Ghaleb
G
Elyamany
Division of Hematology and Transfusion Medicine, Department of Pathology and Laboratory Medicine, University of Calgary/Calgary Laboratory Services (CLS), Calgary, Alberta, Canada.
Meer-Taher
MT
Shabani-Rad
Division of Hematology and Hematologic Malignancies, Tom Baker Cancer Center, University of Calgary, Calgary, Alberta, Canada.
Douglas A
DA
Stewart
Division of Hematology and Transfusion Medicine, Department of Pathology and Laboratory Medicine, University of Calgary/Calgary Laboratory Services (CLS), Calgary, Alberta, Canada.
Adnan
A
Mansoor
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001402:B-Lymphocytes / Q000378:metabolism*; D016000:Cluster Analysis; D015331:Cohort Studies; D019295:Computational Biology; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000378:metabolism* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D012074:Remission Induction; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000378:metabolism*; D016896:Treatment Outcome; D015854:Up-Regulation
D011947:Receptors, Antigen, B-Cell; D051193:Toll-Like Receptors
BCR expression; TLR expression; mantle cell lymphoma; overall survival