Targeting cell adhesion and homing as strategy to cure Waldenström's macroglobulinemia.
Most B-cell malignancies strictly depend on signals from the microenvironment for their survival and proliferation. This niche-dependency can be regarded as their Achilles' heel and provides an excellent target for therapy. Waldenström's macroglobulinemia (WM) is characterized by the accumulation of neoplastic post-germinal center B cells within the bone marrow (BM). Interestingly, one third of the patients carry activating mutations in the chemokine receptor CXCR4, a key mediator of B cell and plasma cell homing to the BM. We have previously shown that signals from the B-cell antigen receptor (BCR) and from chemokine receptors play a central role in controlling the interaction of normal and malignant B cells with their microenvironment by regulating the activity of integrin adhesion molecules. Apart from controlling the homing and retention of lymphocytes within their growth- and survival niches, integrins also emit signals that directly promote cell growth and survival. By analogy to the successful treatment with BTK inhibitors, we propose that targeting pathways controlling integrin-mediated retention of the WM cells in the BM, thereby inducing 'homelessness' (anoikis) by mobilization of the malignant cells from their protective niches, may be an efficient treatment strategy for WM.
Department of Pathology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; Lymphoma and Myeloma Center Amsterdam - LYMMCARE, The Netherlands. Electronic address: s.t.pals@amc.uva.nl.
Steven T
ST
Pals
Department of Hematology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; Lymphoma and Myeloma Center Amsterdam - LYMMCARE, The Netherlands.
Marie José
MJ
Kersten
Department of Pathology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; Lymphoma and Myeloma Center Amsterdam - LYMMCARE, The Netherlands.
Marcel
M
Spaargaren
D000818:Animals; D001853:Bone Marrow / Q000276:immunology*; D002448:Cell Adhesion / Q000235:genetics / Q000276:immunology; D006801:Humans; D016023:Integrins / Q000235:genetics / Q000276:immunology*; D009154:Mutation; D010950:Plasma Cells / Q000276:immunology*; D011947:Receptors, Antigen, B-Cell / Q000276:immunology*; D019718:Receptors, CXCR4 / Q000235:genetics / Q000276:immunology; D059016:Tumor Microenvironment / Q000276:immunology*; D008258:Waldenstrom Macroglobulinemia / Q000235:genetics / Q000276:immunology / Q000628:therapy
C527276:CXCR4 protein, human; D016023:Integrins; D011947:Receptors, Antigen, B-Cell; D019718:Receptors, CXCR4
Adhesion; Bruton's tyrosine kinase; Homing; Integrin; Signaling; Waldenström's macroglobulinemia