Musashi 2 influences chronic lymphocytic leukemia cell survival and growth making it a potential therapeutic target

Florencia Palacios,Xuejing Yang,Jonathan E Kolitz,Nicholas Chiorazzi,Philip Rock,Jeffrey Gardner,Michael G Kharas,Xiao-Jie Yan,Steven L Allen,Kanti R Rai,Shih-Shih Chen,Omar Abdel-Wahab,Stefano Vergani,Gerardo Ferrer,Jaqueline C Barrientos,Richard Burack

doi:10.1038/s41375-020-01115-y

Abstract

Progression of chronic lymphocytic leukemia (CLL) results from the expansion of a small fraction of proliferating leukemic B cells. When comparing the global gene expression of recently divided CLL cells with that of previously divided cells, we found higher levels of genes involved in regulating gene expression. One of these was the oncogene Musashi 2 (MSI2), an RNA-binding protein that induces or represses translation. While there is an established role for MSI2 in normal and malignant stem cells, much less is known about its expression and role in CLL. Here we report for the first time ex vivo and in vitro experiments that MSI2 protein levels are higher in dividing and recently divided leukemic cells and that downregulating MSI2 expression or blocking its function eliminates primary human and murine CLL and mature myeloid cells. Notably, mature T cells and hematopoietic stem and progenitor cells are not affected. We also confirm that higher MSI2 levels correlate with poor outcome markers, shorter time-to-first-treatment, and overall survival. Thus, our data highlight an important role for MSI2 in CLL-cell survival and proliferation and associate MSI2 with poor prognosis in CLL patients. Collectively, these findings pinpoint MSI2 as a potentially valuable therapeutic target in CLL.

Highlights

When performing gene expression profiling (GEP), we found that the RNA-binding protein Musashi 2 (MSI2) was highly expressed in dividing or recently divided cells, defined by the CXCR4DimCD5Bright immunophenotype compared with the resting fraction (RF, CXCR4BrightCD5Dim)
Since MSI2 protein levels are naturally higher in the PF (PB and lymph node (LN)) (Fig. 1B–D) and in in vitro stimulated Chronic lymphocytic leukemia (CLL) cells (Fig. 2), we evaluated the extent that MSI2 levels differ in dividing and recently divided cells compared to undivided cells
Support for MSI2 promoting CLL-cell growth comes from our ex vivo finding that MSI2 expression is upregulated in recently divided CLL cells and our in vitro studies of leukemic cells induced to divide by signals resembling those delivered in the tissue microenvironment where CLLcell birth occurs [40]

Summary

Introduction

The majority of circulating CLL cells are not replicating, a small fraction divides in lymphoid tissues and some of the recently divided leukemic cells migrate and are found in peripheral blood (PB) [4]. Since dividing cells upregulate DNA mutators, such as AID [6,7,8], cells within this intraclonal subset can acquire new DNA abnormalities that could lead to more lethal disease. This makes cells of this intraclonal fraction important targets for therapy

Methods

Results

Conclusion