CXCR4 in Waldenström’s Macroglobulinema: chances and challenges

• Published in: Leukemia 2021-02, Vol.35 (2), p.333-345
• Main Authors: Kaiser, Lisa Marie, Hunter, Zachary R., Treon, Steven P., Buske, Christian
• Format: Article
• Language: English
• Subjects: 631/67/1990/291/1621/1915; 692/699/1541/1990/291/1621/1915; Agammaglobulinaemia Tyrosine Kinase - metabolism; Animals; Bone marrow; Bruton's tyrosine kinase; Cancer; Cancer Research; Care and treatment; Chemokines; Critical Care Medicine; CXCR4 protein; Development and progression; Diagnostic systems; Enzyme inhibitors; Gene expression; Gene mutations; Genes; Genetic aspects; Health aspects; Hematology; Humans; Immunoglobulin M; Intensive; Internal Medicine; Kinases; Lymphocytes B; Lymphoproliferative disorders; Macroglobulinemia; Medicine; Medicine & Public Health; Mutation; MyD88 protein; Neoplasia; Oncology; Patients; Point mutation; Protein-tyrosine kinase; Receptors, CXCR4 - metabolism; Review; Review Article; Signal Transduction; Tyrosine; Waldenstrom Macroglobulinemia - metabolism; Waldenstrom Macroglobulinemia - pathology
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/s41375-020-01102-3

It is one of the major aims in cancer research to improve our understanding of the underlying mechanisms which initiate and maintain tumor growth and to translate these findings into novel clinical diagnostic and therapeutic concepts with the ultimate goal to improve patient care. One of the greater success stories in this respect has been Waldenström’s Macroglobulinemia (WM), which is an incurable B-cell neoplasm characterized by serum monoclonal immunoglobulin M (IgM) and clonal lymphoplasmacytic cells infiltrating the bone marrow. Recent years have succeeded to describe the molecular landscape of WM in detail, highlighting two recurrently mutated genes, the MYD88 and the CXCR4 genes: MYD88 with an almost constant and recurrent point mutation present in over 90% of patients and CXCR4 with over 40 different mutations in the coding region affecting up to 40% of patients. Intriguingly, both mutations are activating mutations leading in the case of CXCR4 to an indelible activation and perpetual signaling of the chemokine receptor. These data have shed light on the essential role of CXCR4 in this disease and have paved the way to use these findings for predicting treatment response to the Bruton tyrosine kinase (BTK) inhibitor ibrutinib and novel therapeutic approaches in WM, which might be transferable to other related CXCR4 positive diseases. Well known for its central role in cancer progression and distribution, CXCR4 is highlighted in this review with regard to its biology, prognostic and predictive relevance and therapeutic implications in WM.