Multiple myeloma (MM) is a B-cell malignancy characterized by abnormal growth and proliferation of plasma cells within the bone marrow. While signals originating from the bone marrow microenvironment are crucial for MM cell growth, explorations into the molecular mechanisms governing MM proliferation have been inadequately addressed. However, results from our lab and others demonstrated the importance of T helper signals in B-cell malignancies and in potentiating BCR signaling via upregulation of CD45 phosphatase activity. Thus, we hypothesized CD45-dependent signaling may be an important factor mediating MM plasma cell growth and proliferation.
To test our hypothesis, we used multiplexed phosphoflow to define CD45 regulation in plasma cells obtained from bone marrow aspirates of MM patients. Preliminary results demonstrated malignant plasma cells had increased CD45 activity with paradoxically less CD45 expression relative to control plasma cells. A potential CD45 ligand, galectin-1, was upregulated in MM plasma cells suggesting enhanced CD45 activity resulted from increased galectin-1:CD45 interaction. Confocal microscopy performed on healthy B cells demonstrated colocalization between CD45 and galectin-1, corroborating galectin-1 as a potential CD45 ligand. Recapitulation of T cell help additionally increased CD45 activity in MM cells and correlated with increased proliferation. In a similar set of experiments, inhibition of CD45, or of its potential ligand galectin-1, reduced the proliferative capacity of MM cells.
Together, our results highlight the importance of T helper cell dependent upregulation of CD45 activity via galectin-1 as a potential molecular mechanism governing MM cell survival. The CD45:galectin-1 interaction warrants further investigation as therapeutic targets.
John Imbery– University of Oslo
Julia Heinzelbecker– University of Oslo
Camilla Myklebust– University of Oslo
Nunzio Bottini– UCSD
Stephanie Stanford– UCSD
Ludvig A. Munthe– University of Oslo
Anders Tveita– University of Oslo
Fredrik Schjesvold– University of Oslo
Geir Tjonnfjord– University of Oslo
Peter Szodoray– University of Oslo
Britt Nakken– University of Oslo