Clonogenic Multiple Myeloma Cells have Shared stemness Signature Associated with Patient Survival

Abstract

Multiple myeloma is the abnormal clonal expansion of post germinal B cells in the bone marrow. It was previously reported that clonogenic myeloma cells are CD138−. Human MM cell lines RPMI8226 and NCI H929 contained 2-5% of CD138− population. In this study, we showed that CD138− cells have increased ALDH1 activity, a hallmark of normal and neoplastic stem cells. CD138−ALDH+ cells were more clonogenic than CD138+ALDH− cells and only CD138− cells differentiated into CD138+ population. In vivo tumor initiation and clonogenic potentials of the CD138− population was confirmed using NOG mice. We derived a gene expression signature from functionally validated and enriched CD138− clonogenic population from MM cell lines and validated these in patient samples. This data showed that CD138− cells had an enriched expression of genes that are expressed in normal and malignant stem cells. Differentially expressed genes included components of the polycomb repressor complex (PRC) and their targets. Inhibition of PRC by DZNep showed differential effect on CD138− and CD138+ populations. The ‘stemness’ signature derived from clonogenic CD138− cells overlap significantly with signatures of common progenitor cells, hematopoietic stem cells, and Leukemic stem cells and is associated with poorer survival in different clinical datasets.

Drug resistance in multiple myeloma: latest findings and new concepts on molecular mechanisms

“…It has been shown that: a)-only CD138 − MM cells have the clonogenic potential and are able to propagate MM tumor in NOD/SCID mice, b)-MMCSCs carry the immunophenotype signature CD138 − /CD19 + /CD20 + /CD27 + , indicating that MMCSCs possess a memory B cell-like phanotype signature arising from a hierarchical pre-malignant plasma cell stage, c)-In a novel 3D model drug resistant MM cells were CD20 + [237], and MMCSCs growth was inhibited by rituximab (anti-CD20 mAb), d)-MMCSCs (CD138 − MM cells) are resistant to dexamethasone, lanalidomide, bortezomib, are enriched in a side population (SP) with high ALDH1 activity and drug efflux pump [238], and recently e)-CD138 − MM cells are ALDH + , have a higher clonogenic potential than CD138 + cells and are able to expand tumor in NOG mice [239]. Several previous studies from Pilarski et al also confirmed presence of clonotypic B cells in MM patients contributing to tumor expansion, relapse and DR [240-242].…”

Prognostic value of deep sequencing method for minimal residual disease detection in multiple myeloma

“…The use of alternative methods for disease assessment such as imaging techniques (positron emission tomography, computed tomography), 47 monitoring of clonogenic MM progenitors, 48,49 or MM circulating tumor cells, 22,49,50 could provide complementary information to MRD and improve the estimation of the risk of progression.…”

CD138-negative myeloma cells regulate mechanical properties of bone marrow stromal cells through SDF-1/CXCR4/AKT signaling pathway

“…Matsui et al first described CD138 negative (CD138 − ) population with greater clonogenic potential than CD138 positive (CD138 + ) myeloma cells [15, 16]. CD138 − clonotypic B cells are also found in the peripheral blood and bone marrow of patients with MM [16, 17] and are associated with poor survival of MM patients [18]. Indeed, successful engraftment of CD138 − subpopulation from MM patients, but not CD138 + , in NOD/SCID mice suggested that CD138 − myeloma cells were the principal myeloma initiating cells [19].…”