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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+ populations. 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.

SUBMITTER: Reghunathan R

PROVIDER: S-EPMC3787153 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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Clonogenic multiple myeloma cells have shared stemness signature associated with patient survival.

Reghunathan Renji R Bi Chonglei C Liu Shaw Cheng SC Loong Koh Tze KT Chung Tae-Hoon TH Huang Gaofeng G Chng Wee Joo WJ

Oncotarget 20130801 8

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+ populations. In vivo tum ...[more]

PMID: 23985559

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Project description:Novel therapies capable of targeting drug resistant clonogenic MM cells are required for more effective treatment of multiple myeloma. This study investigates the cytotoxicity of natural killer cell lines against bulk and clonogenic multiple myeloma and evaluates the tumor burden after NK cell therapy in a bioluminescent xenograft mouse model.The cytotoxicity of natural killer cell lines was evaluated against bulk multiple myeloma cell lines using chromium release and flow cytometry cytotoxicity assays. Selected activating receptors on natural killer cells were blocked to determine their role in multiple myeloma recognition. Growth inhibition of clonogenic multiple myeloma cells was assessed in a methylcellulose clonogenic assay in combination with secondary replating to evaluate the self-renewal of residual progenitors after natural killer cell treatment. A bioluminescent mouse model was developed using the human U266 cell line transduced to express green fluorescent protein and luciferase (U266eGFPluc) to monitor disease progression in vivo and assess bone marrow engraftment after intravenous NK-92 cell therapy.Three multiple myeloma cell lines were sensitive to NK-92 and KHYG-1 cytotoxicity mediated by NKp30, NKp46, NKG2D and DNAM-1 activating receptors. NK-92 and KHYG-1 demonstrated 2- to 3-fold greater inhibition of clonogenic multiple myeloma growth, compared with killing of the bulk tumor population. In addition, the residual colonies after treatment formed significantly fewer colonies compared to the control in a secondary replating for a cumulative clonogenic inhibition of 89-99% at the 20:1 effector to target ratio. Multiple myeloma tumor burden was reduced by NK-92 in a xenograft mouse model as measured by bioluminescence imaging and reduction in bone marrow engraftment of U266eGFPluc cells by flow cytometry.This study demonstrates that NK-92 and KHYG-1 are capable of killing clonogenic and bulk multiple myeloma cells. In addition, multiple myeloma tumor burden in a xenograft mouse model was reduced by intravenous NK-92 cell therapy. Since multiple myeloma colony frequency correlates with survival, our observations have important clinical implications and suggest that clinical studies of NK cell lines to treat MM are warranted.

Dataset Information

Clonogenic multiple myeloma cells have shared stemness signature associated with patient survival.

Publications

Clonogenic multiple myeloma cells have shared stemness signature associated with patient survival.

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