ROR1/CD19 receptor complex promotes growth of mantle cell lymphoma cells independently of the B Cell Receptor-BTK signaling pathway

• Published in: The Journal of immunology (1950) 2019-09, Vol.203 (8), p.2043-2048
• Main Authors: Zhang, Qian, Wang, Hong Y, Liu, Xiaobin, Nunez-Cruz, Selene, Jillab, Mowafaq, Melnikov, Olga, Nath, Kavindra, Glickson, Jerry, Wasik, Mariusz A
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1801327

Inhibitors of Bruton tyrosine kinase (BTK), a kinase downstream of BCR, display remarkable activity in a subset of mantle cell lymphoma (MCL) patients, but the drug resistance remains a considerable challenge. In this study, we demonstrate that aberrant expression of ROR1 (receptor tyrosine kinase-like orphan receptor 1), seen in a large subset of MCL, results in BCR/BTK–independent signaling and growth of MCL cells. ROR1 forms a functional complex with CD19 to persistently activate the key cell signaling pathways PI3K–AKT and MEK–ERK in the BCR/BTK–independent manner. This study demonstrates that ROR1/CD19 complex effectively substitutes for BCR–BTK signaling to promote activation and growth of MCL cells. Therefore, ROR1 expression and activation may represent a novel mechanism of resistance to inhibition of BCR/BTK signaling in MCL. Our results provide a rationale to screen MCL patients for ROR1 expression and to consider new therapies targeting ROR1 and/or CD19 or their downstream signaling pathways for MCL-expressing ROR1.