Musashi 2 Is Overexpressed in Poor Outcome CLL Patients and Their Proliferative Fraction and Silencing This Gene Induces Apoptosis and Increases Cell Adhesion and Movement

The growth of CLL cells stems from a small fraction of dividing CD5+B cells. The size and rate of growth of this proliferative fraction (PF) correlates directly with poor outcome prognostic markers and inversely with time-to-first-treatment. Furthermore, since dividing cells upregulate DNA mutators (AID and APOBEC), the PF can acquire new DNA abnormalities that can lead to more lethal disease. Hence, cells of the PF are important targets for therapy.By gene expression profile analysis, we found that Musashi 2 (MSI2) is highly expressed in the PF (CXCR4DimCD5Bright) compared with the resting fraction (RF) that expresses the reciprocal phenotype (CXCR4BrightCD5Dim). In normal cells, MSI2 binds to mRNA and blocks or enhances protein translation. MSI2 levels are higher in proliferating normal and malignant stem cells and during tumorigenesis. In CLL, high MSI2 mRNA levels associate with poor outcome. Nevertheless, nothing is known about the function of MSI2 in CLL cells. Therefore, we studied the biological role of MSI2 in CLL B cells.We found that CLL B cells express higher levels of MSI2 protein than those of healthy donors (HD). MSI2 levels were higher in U-CLL than M-CLL, and M-CLL B cells expressed more than HD cells, consistent with MSI2 associating with poor prognosis. Within a CLL clone, MSI2 was higher in PF than RF. Also, microenvironment signals that induce B cell proliferation also increased MSI2 protein levels. Consistent with these observations in patients, in vitro...
Source: Blood - Category: Hematology Authors: Tags: 641. CLL: Biology and Pathophysiology, excluding Therapy: Poster I Source Type: research