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.
Julia Heinzelbecker– University of Oslo
Britt Nakken– University of Oslo
Peter Szodoray– Oslo University Hospital
Ludvig A. Munthe– University of Oslo
John Imbery– University of Oslo
Camilla Myklebust– University of Oslo
Anders Tveita– University of Oslo
Geir Tjonnfjord– University of Oslo
Stephanie Stanford– UCSD
Nunzio Bottini– UCSD
Fredrik Schjesvold– University of Oslo