scholarly journals Dynamic balance of multiple myeloma clonogenic side population cell percentages controlled by environmental conditions

2014 ◽  
Vol 136 (5) ◽  
pp. 991-1002 ◽  
Author(s):  
Jianguo Wen ◽  
Wenjing Tao ◽  
Isere Kuiatse ◽  
Pei Lin ◽  
Yongdong Feng ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Environmental Conditions ◽  
Side Population ◽  
Dynamic Balance ◽  
Side Population Cell

scholarly journals PIWIL1 Drives Chemoresistance in Multiple Myeloma by Modulating Mitophagy and the Myeloma Stem Cell Population

2022 ◽  
Vol 11 ◽  
Author(s):  
Yajun Wang ◽  
Lan Yao ◽  
Yao Teng ◽  
Hua Yin ◽  
Qiuling Wu
Keyword(s):  
Multiple Myeloma ◽  
Drug Resistance ◽  
Stem Cell ◽  
Cell Population ◽  
Side Population ◽  
Chemotherapeutic Agents ◽  
Stem Cell Population ◽  
Exact Function

As an important member of the Argonaute protein family, PIWI-like protein 1 (PIWIL1) plays a key role in tumor cell viability. However, the exact function of PIWIL1 in multiple myeloma (MM) and the underlying mechanism remain unclear. Here, we revealed that PIWIL1 was highly expressed in myeloma cell lines and newly diagnosed MM patients, and that its expression was notably higher in refractory/relapsed MM patients. PIWIL1 promoted the proliferation of MM cells and conferred resistance to chemotherapeutic agents both in vitro and in vivo. More importantly, PIWIL1 enhanced the formation of autophagosomes, especially mitophagosomes, by disrupting mitochondrial calcium signaling and modulating mitophagy-related canonical PINK1/Parkin pathway protein components. Mitophagy/autophagy inhibitors overcome PIWIL1-induced chemoresistance. In addition, PIWIL1 overexpression increased the proportion of side population (SP) cells and upregulated the expression of the stem cell-associated genes Nanog, OCT4, and SOX2, while its inhibition resulted in opposite effects. Taken together, our findings demonstrated that PIWIL1 induced drug resistance by activating mitophagy and regulating the MM stem cell population. PIWIL1 depletion significantly overcame drug resistance and could be used as a novel therapeutic target for reversing resistance in MM patients.

Multiple Myeloma Stem Cells and Plasma Cells Display Distinct Drug Sensitivities.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2476-2476 ◽  
Author(s):  
William Matsui ◽  
Carol Ann Huff ◽  
Qiuju Wang ◽  
James P. Barber ◽  
B. Douglas Smith ◽  
...  
Keyword(s):  
Stem Cells ◽  
Multiple Myeloma ◽  
Antitumor Agents ◽  
Plasma Cells ◽  
Clinical Symptoms ◽  
Side Population ◽  
Cell Surface Antigens ◽  
Intracellular Enzyme ◽  
Major Activity ◽  
Rpmi 8226

Abstract We recently demonstrated that multiple myeloma (MM) is organized in a hierarchical manner in which clonogenic MM progenitors or stem cells resembling post-germinal B cells give rise to MM plasma cells (PC). To study the potential biologic differences between MM stem cells and MM PC, we examined each cellular subset for characteristics found in normal stem cells as well as their responses to various antitumor agents. The human MM cell lines RPMI 8226 and NCI-H929 were initially studied as we previously found that they recapitulate clinical MM specimens and consist of distinct cell populations based on the expression of the PC surface antigen CD138; CD138+ cells resemble typical MM PC, whereas CD138neg cells express B cell surface antigens and have greater clonogenic capacity. Examination of these cellular subpopulations by flow cytometry demonstrated that CD138neg cells were smaller and less granular by light scatter than CD138+ PC and expressed higher levels of the intracellular enzyme aldehyde dehydrogenase that is present in normal hematopoietic progenitors with self-renewal potential. Furthermore, cells expressing the side population phenotype after staining with the DNA binding dye Hoechst 33342 were exclusively CD138neg. We also investigated the effects of different clinically applicable agents on CD138+ and CD138neg cells. CD138+ and CD138neg cells isolated from RPMI 8226 and NCI-H929 cells by fluorescence activated cell sorting were treated with dexamethasone (dex, 100nM), bortezomib (velcade, 10nM), CC5013 (revlimid, 1μM), rituximab (10μg/ml) or alemtuzumab (campath,10μg/ml) for 72 hours followed by plating in methylcellulose to assess clonogenic capacity. CD138+ PC were significantly inhibited by dex (27 ± 11% recovery compared to untreated control cells), velcade (14 ± 6%) and revlimid (44 ± 27%), whereas rituximab (92 ± 25%) and campath (97 ± 18%) had little activity. In contrast, clonogenic growth of CD138neg cells was not significantly inhibited by dex (82 ± 19%), velcade (88 ± 29%), or revlimid (91 ± 14%), but was significantly decreased by rituximab (63 ± 22%) and campath (47 ± 27%). Similarly, clonogenic MM growth of CD138neg cells from 4 clinical MM samples was not affected by dex (84 ± 9%), velcade (82 ± 24%), or revlimid (93 ± 11%), but was significantly inhibited by rituximab (19 ± 7%) or campath (15 ± 11%). Clonogenic MM precursors may be distinguished from MM PC by a variety of biological parameters typically expressed by normal stem cells. Furthermore, these cellular subsets have different susceptibilities to a variety of clinical agents, and agents with activity against MM PC may be ineffective against MM stem cells. Moreover, agents without activity agasint MM PC may have major activity against MM stem cells. The divergent sensitivities of MM stem cells and PC may explain the dramatic, but transient, responses seen with many agents. Therapeutic strategies that result in long-term remissions may require the inhibition of both MM PC to reduce clinical symptoms and MM stem cells responsible for relapse.

scholarly journals Cardiac neural crest cells contribute to the dormant multipotent stem cell in the mammalian heart

2005 ◽  
Vol 170 (7) ◽  
pp. 1135-1146 ◽  
Author(s):  
Yuichi Tomita ◽  
Keisuke Matsumura ◽  
Yoshio Wakamatsu ◽  
Yumi Matsuzaki ◽  
Isao Shibuya ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Neural Crest ◽  
Side Population ◽  
Side Population Cell ◽  
Multi Drug Resistance ◽  
Multipotent Stem Cells ◽  
Cardiac Neural Crest ◽  
Differentiated Cells ◽  
Undifferentiated Cells ◽  
The Right

Arodent cardiac side population cell fraction formed clonal spheroids in serum-free medium, which expressed nestin, Musashi-1, and multi-drug resistance transporter gene 1, markers of undifferentiated neural precursor cells. These markers were lost following differentiation, and were replaced by the expression of neuron-, glial-, smooth muscle cell–, or cardiomyocyte-specific proteins. Cardiosphere-derived cells transplanted into chick embryos migrated to the truncus arteriosus and cardiac outflow tract and contributed to dorsal root ganglia, spinal nerves, and aortic smooth muscle cells. Lineage studies using double transgenic mice encoding protein 0–Cre/Floxed-EGFP revealed undifferentiated and differentiated neural crest-derived cells in the fetal myocardium. Undifferentiated cells expressed GATA-binding protein 4 and nestin, but not actinin, whereas the differentiated cells were identified as cardiomyocytes. These results suggest that cardiac neural crest-derived cells migrate into the heart, remain there as dormant multipotent stem cells—and under the right conditions—differentiate into cardiomyocytes and typical neural crest-derived cells, including neurons, glia, and smooth muscle.

A Recombinant HLA Class I-Specific Single-Chain Fv Diabody Can Target Cancer Stem Cell-Like Side Population Cells in Multiple Myeloma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2799-2799
Author(s):  
Akishige Ikegame ◽  
Shuji Ozaki ◽  
Daisuke Tsuji ◽  
Takeshi Harada ◽  
Shingen Nakamura ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Flow Cytometry ◽  
Stem Cell ◽  
Side Population ◽  
Hla Class I ◽  
Class I ◽  
Chemotherapeutic Drugs ◽  
Single Chain ◽  
Single Chain Fv ◽  
Rpmi 8226

Abstract Abstract 2799 Poster Board II-775 Multiple myeloma (MM) remains an incurable disease despite high overall response rates induced by combination therapy of chemotherapeutic drugs and new agents such as thalidomide, lenalidomide, and bortezomib. Recently, the existence of cancer stem cells is proposed for several tumors including MM, and such cells are considered as an important target for curative therapy. The side population (SP) cells are identified by their ability to efflux Hoechst 33342 dye, which represent a small fraction with stem cell properties. Our previous studies have demonstrated that MM cells expressed HLA class I at high levels than normal hematopoietic cells, and that antibodies against HLA class I specifically induced MM cell death by Rho-mediated actin aggregation. In this study, we characterized SP fraction in MM cell lines (RPMI 8226, U266, and MM.1S) and primary MM cells (n=3) by flow cytometry, and investigated the efficacy of chemotherapeutic drugs as well as a recombinant single-chain Fv diabody specific to HLA class I (C3B3-DB, Chugai Pharmaceutical Co., Ltd, Tokyo, Japan). MM cell lines and primary MM cells contained a distinct fraction of SP cells ranging from 0.01% to 0.6% of the gated cells, which was confirmed by disappearance after treatment with verapamil. Treatment with melphalan (10 μM, 48 hours) decreased the percentage of non-SP cells (16.7% to 3.9%) but not of SP cells (0.6% to 0.7%) in RPMI 8226. In contrast, treatment with C3B3-DB (1 μg/ml, 48 hours) caused a significant reduction in both non-SP cells (16.7% to 4.0%) and SP cells (0.6% to 0.3%) in RPMI 8226. Similar results were observed in primary MM cells enriched from patient bone marrow cells by negative selection with antibody cocktail. Next, we isolated SP cells and non-SP cells in RPMI 8226 using a cell sorter, and characterized in detail. SP cells exhibited elevated levels of ABCG2 and low levels of CD138 compared with non-SP cells, but HLA class I was expressed at high levels in both SP and non-SP cells by flow cytometry. Annexin/PI assay showed that SP cells were 1.5- and 2.0-fold more resistant to melphalan and bortezomib than non-SP cells. Whereas both SP cells and non-SP cells showed similar sensitivity to C3B3-DB. Methylcellulose colony-forming assay showed that SP cells have a higher potential for colony formation (numbers of colonies, 13.0±1.0) than non-SP cells (1.3±0.6), and the colony formation of SP cells was significantly inhibited by C3B3-DB (0.7±0.6, p<0.01). Notably, RPMI 8226 cells expressed the pluripotency-associated transcription factors including Oct3/4, Sox2, and Nanog as detected by RT-PCR, but only Sox2 mRNA expression was decreased at 6 hours after C3B3-DB treatment. Furthermore, when C3B3-DB-treated SP cells were inoculated subcutaneously in SCID mice (n=4), there was a significant decrease in a tumor volume as compared with untreated SP cells (679±148mm3 vs 3217±562 mm3, p<0.01). SP cell analysis of these tumors showed that the percentage of SP fraction of C3B3-DB-treated SP cell tumors was significantly low (0.01%) compared with that of untreated SP cell tumors (0.33%). These results indicate that C3B3-DB has a potential activity for eradicating MM cancer stem cell-like SP cells, and that the molecular targeting of such drug-resistant cells provides an important strategy for improving the efficacy of current therapies in MM. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Akt Signaling Regulates Side Population Cell Phenotype via Bcrp1 Translocation

2003 ◽  
Vol 278 (40) ◽  
pp. 39068-39075 ◽  
Author(s):  
Masaki Mogi ◽  
Jiang Yang ◽  
Jean-Francois Lambert ◽  
Gerald A. Colvin ◽  
Ichiro Shiojima ◽  
...  
Keyword(s):  
Side Population ◽  
Akt Signaling ◽  
Side Population Cell ◽  
Cell Phenotype
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