The underlying mechanism of chronic proliferation in B-cell malignancies is unresolved, however, several common characteristics exist. First, signaling through the B-cell receptor (BCR) is crucial, and secondly, T-helper signals from the microenvironment contribute to proliferation of malignant B-cells in diseases such as chronic lymphocytic leukemia (CLL) and multiple myeloma (MM) (Os et al, 2013, Wang et al., 2017).
We discovered a mechanism where T-cell help enhance the ability of B-cells to signal through the BCR (Szodoray et al, 2016). We found that T-helper signals regulate CD45 phosphatase activity in B-cells, which is a key positive regulator of the BCR-signaling and proliferation machinery. Mechanistically, we show that T-cell mediated Galectin-1 surface binding upregulate CD45 phosphatase activity, and thus, T-helper signals enhance the ability of B-cells to respond to antigenic stimulation, leading to proliferation and survival through CD45 activity regulation.
For malignant B-cells, inhibition of CD45 activity significantly downregulated T-cell mediated BCR-signaling and proliferation in CLL. Moreover, inhibiting Galectin-1 binding to malignant B-cells reduced cell proliferation, however, this was more prominent for IKAROS+ CLL-cells. Interestingly, upregulation of Galectin-1 surface expression was mainly restricted to IKAROS+ CLL-cells upon CD40L-stimulation, suggesting a link between IKAROS and CD45 phosphatase activity through Galectin-1 modulation.. These data suggest that expression of the CD45 ligand Galectin-1, and thus CD45 phosphatase activity may be under the control of IKAROS.
We propose that regulation of CD45 phosphatase activity, survival and proliferation capacity of malignant B-cells may be controlled by CD45-ligand(s) such as Galectin-1.