Ibrutinib inhibits CD20 upregulation on CLL B cells mediated by the CXCR4/SDF-1 axis

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Publikace nespadá pod Lékařskou fakultu, ale pod Středoevropský technologický institut. Oficiální stránka publikace je na webu muni.cz.

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PAVLASOVÁ Gabriela BORSKÝ Marek ŠEDA Václav ČERNÁ Kateřina OSIČKOVÁ Jitka DOUBEK Michael MAYER Jiří CALOGERO Raffaele TRBUŠEK Martin POSPÍŠILOVÁ Šárka DAVIDS Matthew S. KIPPS Thomas J. BROWN Jennifer R. MRÁZ Marek

Rok publikování 2016
Druh Článek v odborném periodiku
Časopis / Zdroj Blood
Fakulta / Pracoviště MU

Středoevropský technologický institut

Citace
www http://www.bloodjournal.org/content/bloodjournal/128/12/1609.full.pdf
Doi http://dx.doi.org/10.1182/blood-2016-04-709519
Obor Onkologie a hematologie
Klíčová slova CHRONIC LYMPHOCYTIC-LEUKEMIA; MARROW STROMAL CELLS; DOWN-REGULATION; PLUS RITUXIMAB; IN-VIVO; RECEPTOR; EXPRESSION; APOPTOSIS; ACTIVATION; BTK
Přiložené soubory
Popis Agents targeting B-cell receptor (BCR) signaling-associated kinases such as Bruton tyrosine kinase (BTK) or phosphatidylinositol 3-kinase can induce mobilization of neoplastic B cells from the lymphoid tissues into the blood, which makes them potentially ideal to combine with anti-CD20 monoclonal antibodies (such as rituximab, obinutuzumab, or ofatumumab) for treatment of B-cell lymphomas and chronic lymphocytic leukemia (CLL). Here we show that interactions between leukemia cells and stromal cells (HS-5) upregulate CD20 on CLL cells and that administering ibrutinib downmodulates CD20(MS4A1) expression in vivo. We observed that CLL cells that have recently exited the lymph node microenvironment and moved into the peripheral blood (CXCR4(dim)CD5(bright) subpopulation) have higher cell surface levels of CD20 than the cells circulating in the bloodstream for a longer time (CXCR4(bright)CD5(dim) cells). We found that CD20 is directly upregulated by CXCR4 ligand stromal cell-derived factor 1 (SDF-1 alpha, CXCL12) produced by stromal cells, and BTK-inhibitor ibrutinib and CXCR4-inhibitor plerixafor block SDF-1 alpha-mediated CD20 upregulation. Ibrutinib also downmodulated Mcl1 levels in CLL cells in vivo and in coculture with stromal cells. Overall, our study provides a first detailed mechanistic explanation of CD20 expression regulation in the context of chemokine signaling and microenvironmental interactions, which may have important implications for microenvironment-targeting therapies.
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