Extracellular calcium sensing promotes human B-cell activation and function

Aberrant interferon-signaling is associated with aggressive chronic lymphocytic leukemia

“…Activated mitochondria also make ROS, which can be measured by flow cytometry with DCFH. 36 A hallmark of aggressive CLL cells is their enhanced responsiveness to environmental signals 30,37 and increased ROS levels in these cells may reflect these signaling processes. It seems unlikely that corruption of IFN-signaling in aggressive tumor cells is unique to CLL.…”

The B-cell calcium sensor predicts progression of chronic lymphocytic leukemia

“…1 Consistent with this hypothesis, changes in CD83 surface expression 4 h after stimulation by phorbol esters 2 (which mimic aspects of antigenic signaling…”

“…In contrast to normal B cells, JNK was often phosphorylated (consistent with activation) in CLL samples, and expression of phosphorylated 46 and 54 kDa JNK isoforms correlated inversely with Ca o 2 þ responsiveness (Figures 2c and d). The specific JNK inhibitor, SP600125, 5 restored Ca o 2 þ -induced Ca i 2 þ release (Figure 2e) as well as transcription and translation of CD83 (Figures 2f and g), a downstream target of the B-cell Ca o S. 2 These results support a possible inhibitory effect of activated JNK on the Ca o S in indolent CLL cells and an association of intact Ca o 2 þ sensing with the absence of JNK-mediated inhibition in aggressive cells, perhaps reflecting exposure of CLL cells in vivo to immunoreceptor ligands that can activate JNK, 1 as well as impaired JNK functioning that is known to accompany cancer progression. 6 These results are consistent with recent findings that high-risk CLL cells respond more strongly to activation of immunoreceptors, including the B-cell receptor 7 and Toll-like receptors.…”

“…2 In contrast to normal B cells, nearly half (23/51) of the CLL samples examined (with approval from the Sunnybrook Health Sciences Center Research Ethics Board) did not release intracellular calcium (Ca i 2 þ ) in response to CaCl 2 (labeled Ca o 2 þ non-responders) ( Table 1; Figure 1a). This impaired Ca o S activity was not due to decreased stores of Ca i 2 þ in the endoplasmic reticulum, as the Ca 2 þ ATPase inhibitor, thapsigargin, was able to mobilize Ca i 2 þ in these cells (not shown).…”

“…To further address this hypothesis, following a brief period of culture in Ca 2 þ (to trigger the Ca o 2 þ sensor) or in Ca 2 þ -free media (to prevent Ca o 2 þ sensor activation), CLL cells were activated with interleukin-2 and the Toll-like receptor-7 agonist, S28690, in Ca 2 þ -containing AIM-V media (to allow proper functioning of downstream signaling pathways that depend on calcium release-activated calcium channels interleukin-2 and S28690) 2 (Figures 1d and e) or survival under harsh culture conditions (Figure 1f).…”