Presence of Hoechst low side populations in multiple myeloma

Loh, Yen Siew; Mo, Sui-Lin; Brown, Ross; Yamagishi, Tetsuo; Shi, Yang; Joshua, Douglas; Roufogalis, Basil D.; Sze, Daniel Man-Yuen

doi:10.1080/10428190802272676

Cited by 29 publications

(34 citation statements)

References 15 publications

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“…[6][7][8][9] In MM, the distinct fraction of SP cells has been detected in both MM cell lines and primary MM cells. 10 Matsui et al 11 have found the clonogenic property and drug resistance in SP fraction of MM cells, and reported the relationship between SP fraction and CD138 À phenotype. Recently, Jakubikova et al 12 have shown the clonogenic potential of SP cells, although they observed the heterogeneity in CD138 expression of SP cells.…”

Section: Introductionmentioning

confidence: 99%

Small molecule antibody targeting HLA class I inhibits myeloma cancer stem cells by repressing pluripotency-associated transcription factors

et al. 2012

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Section: Introductionmentioning

confidence: 99%

Small molecule antibody targeting HLA class I inhibits myeloma cancer stem cells by repressing pluripotency-associated transcription factors

et al. 2012

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“…2,3 One reason for this high rate of relapse even after multimodal and/or high dose chemotherapy plus autologous stem cell transplantation might be the persistence of myeloma stem cells in the bone marrow, since these cells seem to escape standard chemotherapeutic agents. [4][5][6] As a consequence, MM remains essentially incurable by conventional anti-tumor therapy and patients continue to have a median survival of only 5 years. 7 New therapeutic targets, expressed by the bulk of end-stage myeloma cells as well as their dormant progenitors, are needed for the development of treatments capable of eradicating minimal residual disease and allowing for increased rate of cures or at least prolonged remissions.…”

Section: Introductionmentioning

confidence: 99%

Surface molecule CD229 as a novel target for the diagnosis and treatment of multiple myeloma

Atanackovic¹,

Panse²,

Hildebrandt³

et al. 2011

Haematologica

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The online version of this article has a Supplementary Appendix. BackgroundTo date, multiple myeloma remains an incurable malignancy due to the persistence of minimal residual disease in the bone marrow. In this setting, monoclonal antibodies against myelomaspecific cell surface antigens represent a promising therapeutic approach, which is however hampered by a lack of appropriate target structures expressed across all pathogenic myeloma cell populations. We, therefore, investigated functionally relevant immunoreceptors specifically associated with myeloma cells as well as their clonogenic precursors. Design and MethodsPotential target proteins were identified using antibody arrays against phosphorylated immunoreceptors with lysates from myeloma cell lines. CD229 expression was confirmed in primary myeloma cells by reverse transcriptase polymerase chain reaction, western blot, fluorescence-activated cell sorting, and immunohistochemistry. Apoptosis, clonogenic growth, and sensitivity to chemotherapy were determined following short-interfering RNA-mediated downregulation of CD229. Antibody-dependent cellular and complement-dependent cytotoxicity were analyzed using a monoclonal antibody against CD229 to demonstrate the antigen's immunotherapeutic potential. ResultsOur screening assay identified CD229 as the most strongly over-expressed/phosphorylated immunoreceptor in myeloma cell lines. Over-expression was further demonstrated in the CD138-negative population, which has been suggested to represent myeloma precursors, as well as on primary tumor cells from myeloma patients. Accordingly, CD229 staining of patients' bone marrow samples enabled the identification of myeloma cells by flow cytometry and immunohistochemistry. Down-regulation of CD229 led to a decreased number of viable myeloma cells and clonal myeloma colonies, and enhanced the anti-tumor activity of conventional chemotherapeutics. Targeting CD229 with a monoclonal antibody resulted in complement-and cell-mediated lysis of myeloma cells. ConclusionsOur results demonstrate that the immunoreceptor CD229 is specifically over-expressed on myeloma cells including their clonogenic precursors and contributes to their malignant phenotype. Monoclonal antibodies against this protein may represent a promising diagnostic and immunotherapeutic instrument in this disease. Haematologica 2011;96(10):1512-1520. doi:10.3324/haematol.2010 Surface molecule CD229 as a novel target for the diagnosis and treatment of multiple myeloma

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“…Nonetheless, our results on MM patient samples indicate that SP cells are heterogeneous for CD138 antigen expression (J.J., unpublished observations, September 2009), predominantly with lower expression of CD138, similar to a previous report. 37 Another study shows correlation of the CD138 Ϫ phenotype in MM cells with their trend to become apoptotic and fail to grow in vitro, 38 which raises the possibility that the status of CD138 expression in SP cells may exhibit differences depending on the conditions to which the tumor cells are exposed.Conflicting results have also been obtained regarding the SP cell division kinetics, because some groups identify the SP fraction as slowly proliferating cells 26,39 whereas others observe a high proliferation rate in SP cells. 25,40 Our data revealed that MM SP cells had a higher proliferation index/rate than MP cells.…”

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confidence: 99%

Lenalidomide targets clonogenic side population in multiple myeloma: pathophysiologic and clinical implications

Jakubíková

Adamia

Kost‐Alimova

et al. 2011

Blood

142

168

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IntroductionMultiple myeloma (MM), a malignancy hallmarked by accumulation of malignant plasma cells in the bone marrow, remains largely incurable despite the use of conventional and novel therapies. 1 The bone marrow (BM) microenvironment promotes tumor cell growth, survival, and confers drug resistance against conventional agents. 2 Although currently available anti-MM strategies have been effective in targeting the bulk of tumor cells, it has been postulated that a tumor-initiating subpopulation or cancer stem cell persists, which may be responsible for eventual relapses. 3 Side population (SP) cells are an enriched source of cancer-initiating cells with stem cell properties, which have been identified in solid tumors, as well as in hematopoietic malignancies. [4][5][6][7][8] The SP cells show a distinct ''low-staining pattern" with the Hoechst 33342 dye. 9 Importantly, SP cells possess the ability to generate non-SP cells both in vitro and in vivo, and are associated with chemoresistance and tumorigenicity in vivo. 4,10 The prevalence and biologic function of SP cells in MM are not fully defined.In the late 1990s, thalidomide was introduced to the treatment of relapsed/refractory MM; however, its effect in patients is associated with dose-and duration-dependent side effects. 11,12 Since then, more potent immunomodulatory drugs (IMiDs), such as lenalidomide, have been introduced. Lenalidomide has been approved for the treatment of both myelodysplasia with deletion of chromosome 5q and for relapsed MM, specifically in combination with dexamethasone. 12,13 Although IMiDs act directly on tumor cells, block adherence to bone marrow stromal cells (BMSCs), modulate angiogenesis and cytokines, and up-regulate host antitumor immunity, the molecular mechanism for their action remains largely undefined, and it is unclear whether they target SP cells in MM. [14][15][16][17][18] In this study, we identified SP cells in MM cell lines as well as in primary MM tumor cells by flow cytometry-based Hoechst 33342 staining, and showed heterogeneity in the percentage of SP cells, as well as the lack of strict correlation between SP fraction and CD138 Ϫ status. SP cells exhibited clonogenic and tumorigenic potential; and importantly, lenalidomide significantly decreased the percentage and clonogenicity of SP cells at clinically relevant concentrations. Moreover, lenalidomide only slightly altered expression of drug-resistant transporter ABCG2 with no effect on functional activity of BCRP1 efflux pump. Modulation of diverse signaling cascades in SP cells by lenalidomide, including changes in Akt, GSK-3␣/␤, MEK1, c-Jun, p53, and p70S6K phosphorylation was observed. Adherence to BMSCs increased the percentage, viability, and proliferation potential of SP cells. Interestingly, both lenalidomide and thalidomide attenuated this stimulatory effect of BMSCs by significantly decreasing SP cell percentages. Therefore, our studies provide insight toward developing novel strategies Submitted February 5, 2010; accepted October 10, 2010. Prepub...

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Presence of Hoechst low side populations in multiple myeloma

Cited by 29 publications

References 15 publications

Small molecule antibody targeting HLA class I inhibits myeloma cancer stem cells by repressing pluripotency-associated transcription factors

Small molecule antibody targeting HLA class I inhibits myeloma cancer stem cells by repressing pluripotency-associated transcription factors

Surface molecule CD229 as a novel target for the diagnosis and treatment of multiple myeloma

Lenalidomide targets clonogenic side population in multiple myeloma: pathophysiologic and clinical implications

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