Microvesicles in CLL: predictor of disease progression/relapse

Tumor-secreted extracellular vesicles (EVs) including microvesicles (MVs) and exosomes, classified according to their sub-cellular origin [1], are critical mediators of intercellular communication between malignant cells and cells in local and distant microenvironments supporting metastatic niche formation. Clinically, EVs may be biomarkers and novel therapeutic targets that reflect cancer progression, and in particular for predicting and preventing metastatic development [2]. Different biological circumstances under which MV formation has been observed reflect the diversity of their biogenesis. Thus, cellular activation, transformation, stress or programmed cell death are associated with a varying MV production output and their biologic features [3]. Previously, we identified increased plasma levels of predominantly platelet/megakaryocyte-derived MVs in early stage chronic lymphocytic leukemia (CLL) and also documented a phenotypic shift towards more leukemic B-cell-derived MVs with advanced disease stages [4]. Most recently, we studied dynamics of MV generation in vitro by CLL B-cells and in vivo in CLL patients, and their potential use as predictor for CLL progression, therapeutic response and relapse [5]. We find that while CLL B-cells are capable of generating MVs in vitro, CLL B-cells with unmutated IGVH produce higher levels of MVs with B-cell receptor (BCR)-ligation. Further analysis suggests that the tonic BCR signal in CLL B-cells may not be the only factor influencing spontaneous shedding of MVs, as targeting the BCR signal could not block MV production from CLL B-cells, whereas it is known to block exosome production [6]. However, the reduction of CLL plasma MVs following BCRtargeted therapy reinforces the possibility that plasma MV levels can be biomarkers for CLL disease status. Of relevance, MV production from CLL B-Cells is likely to be complicated involving multiple intrinsic and/or tumor microenvironmental factors. Depending on the cell type, membrane MVs may be rich in cell-specific lineage markers [7, 8]. Interestingly, CLL B-cells generate primarily CD52+ MVs, but not the B-cell lineage-specific marker CD19+ MVs, as we have found in vitro with CLL B-cells. This latter result was similar with or without in vitro BCR stimulation and importantly, MVs from CLL plasma. In partial explanation we found that both normal Band CLL B-cells express significantly higher levels of CD52 than CD19 while the CD52 expression levels on normal B-cells were about threefold higher than CLL B-cells. Given this, we hypothesized that lower levels of CD52 on CLL B-cells are a result of shedding primarily CD52+ MVs. Indeed, expression levels of CD52, but not CD19, on CLL B-cells were reduced significantly following 72-hour culture accompanied by increased production of CD52+ MVs. Further analysis suggests that shedding of CD52+ MVs is a physiologic characteristic of human B-lymphocytes. Consistent with the above observations, an increase of plasma CD52+ MV level was noted in 7 of 9 follow-up untreated CLL patients as they progressed from a more indolent phase; while no significant alteration of CD52+ MV levels was discernible in CLL patients with stable disease. These early findings indicate that plasma levels of CD52+ MVs can be a progression biomarker but do need further validation in much larger CLL cohorts. Editorial