The Role Of Proliferating Stem

Topic: Myeloma and other monoclonal gammopathies — Biology & translational research

Background:Multiple myeloma (MM) stands as an incurable and markedly heterogeneous hematological malignancyderived from plasma cells. The management and comprehension of relapsed or refractory multiple myeloma(RRMM) continues to pose a significant challenge. Cancer relapse post-therapy is believed to involve cellsexhibiting stem-like characteristics, marked by high proliferation and indefinite self-renewal.

Aims:To provides a comprehensive characterization of heterogenous features and hierarchical states of malignantplasma cells (PCs) in patients with plasma cell disorders (PCDs), including monoclonal gammopathy ofundetermined significance (MGUS), newly diagnosed MM (NDMM), and RRMM.

Methods:From February 2014 to November 2021, bone marrow mononuclear cells (BMMC) were collected for scRNA-seq from four patients with MGUS, five with NDMM and five with RRMM at Department of hematology,Zhongshan Hospital, Fudan University. For proteomic analysis of CD138+ plasma cells, a total of 144 bonemarrow (BM) aspirate samples were obtained from 140 patients with PCDs at Zhongshan Hospital, FudanUniversity. This dataset included 56 MGUS samples, 8 SMM samples, 63 NDMM samples, and 17 RRMMsamples. Additionally, scRNA-seq data from eight healthy BM donors (normal PCs number=386) wereretrieved from the Human Cell Atlas (HCA) data portal (http://www.altanalyze.org/ICGS/HCA/Viewer.php) toestablish a reference copy number variation (CNV) profile for comparison with malignant PCs. The CoMMpassstudy, a prospective investigational clinical trial (NCT01454297) assessing the transcriptomic profile of NDMMpatients, conducted by the Multiple Myeloma Research Foundation (MMRF), provided the datasets of theinterim analysis 15 used in this study. Furthermore, the bulk microarray profiles from GSE24080 and GSE2113were utilized to verify the prognostic value of DERL3 and LGALS1 for MM patients. For in vitro experiment,quantitative real-time polymerase chain reaction (qRT-PCR) and western blot (WB), colony formation assay,side population cells (SPs), cell proliferation analysis, and apoptosis analysis were all conducted.

Results:We identified a state of malignant plasma cells characterized by high stemness score, a greater occurrence ofthe S phase of the cell cycle, and increased proliferation originating from RRMM. This state has beendesignated as proliferating stem-like plasma cells (PSPCs). NUCKS1 (nuclear casein kinase and cyclin-dependent kinase substrate 1) was identified as the gene marker representing the stemness of PSPCs, evidentat both transcript and translational levels. Comparison of differentially expressed genes among various plasmacell states revealed a significant elevation in LGALS1 expression in PSPCs. Survival analysis on the MMRFCoMMpass dataset and GSE24080 dataset established LGALS1 as a gene associated with unfavorableprognostic implications for MM. Ultimately, we discovered three specific ligand-receptor pairs within the MKsignaling pathway network that play distinct roles in facilitating efficient cellular communication betweenPSPCs and the surrounding microenvironment cells.

Summary/Conclusion:Our research provides a theoretical framework for comprehending the attributes of stem-like plasma cells anduncovers potential targets in patients with RRMM.

Keywords: Plasma cells, Myeloma, Stem cell marker, relapsed/refractory

https://clin.larvol.com/abstract-detail/EHA 2024/70979609