New pieces in the BTKi resistance puzzle

In this issue of Blood, Chen et al¹ report about novel mechanisms of ibrutinib resistance related to BTK Cys481 point mutations in Waldenström macro-globulinemia (WM). They transfected WM and diffuse large B-cell lymphoma (DLBCL) cells with vectors containing wild-type (BTK^WT) or Cys481Ser mutated (BTK^Cys481Ser) BTK, and examined effects of the transfected genes on ibrutinib sensitivity and signaling pathways, especially on ERK activation. The authors report that BTK^Cys481Ser promotes ibrutinib resistance via reactivation of ERK1/2 signaling (see figure). Next, they examined how WM and DLBCL cells carrying BTK^Cys481Ser can confer survival benefit to BTK^WT cells, an important question because BTK resistance mutations often only affect a sub-population of the malignant B cells. A prosurvival effect on WT cells was seen when mixing mutated and WT cells, which apparently did not depend on cell-cell contact, as demonstrated in micropore filter experiments to separate BTK^WT from BTKCys481Ser cells. In this setting, BTKCys481Ser cells still conferred protection of BTK^WT cells in a paracrine fashion, via secretion of cytokines, especially interleukin-6 (IL-6) and IL-10, which were found to be elevated in supernatants from BTKCys481Se but not from BTK^WT cells.