scholarly journals Identification and gene expression analysis of the side population subclone in mantle cell lymphoma

2017 ◽  
Vol 35 ◽  
pp. 284-284
Author(s):  
V. Kuci Emruli ◽  
R. Rosenquist ◽  
C. Sundström ◽  
E. Cordero ◽  
K. Pietras ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mantle Cell Lymphoma ◽  
Expression Analysis ◽  
Gene Expression Analysis ◽  
Cell Lymphoma ◽  
Side Population ◽  
Mantle Cell

Comparative gene expression analysis of zebrafish and mammals identifies common regulators in hematopoietic stem cells

Blood ◽  
2010 ◽  
Vol 115 (2) ◽  
pp. e1-e9 ◽  
Author(s):  
Isao Kobayashi ◽  
Hiromasa Ono ◽  
Tadaaki Moritomo ◽  
Koichiro Kano ◽  
Teruyuki Nakanishi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Expression Analysis ◽  
Gene Expression Analysis ◽  
Side Population ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Cell Junction ◽  
Hematopoietic Stem

Abstract Hematopoiesis in teleost fish is maintained in the kidney. We previously reported that Hoechst dye efflux activity of hematopoietic stem cells (HSCs) is highly conserved in vertebrates, and that Hoechst can be used to purify HSCs from teleost kidneys. Regulatory molecules that are strongly associated with HSC activity may also be conserved in vertebrates. In this study, we identified evolutionarily conserved molecular components in HSCs by comparing the gene expression profiles of zebrafish, murine, and human HSCs. Microarray data of zebrafish kidney side population cells (zSPs) showed that genes involved in cell junction and signal transduction tended to be up-regulated in zSPs, whereas genes involved in DNA replication tended to be down-regulated. These properties of zSPs were similar to those of mammalian HSCs. Overlapping gene expression analysis showed that 40 genes were commonly up-regulated in these 3 HSCs. Some of these genes, such as egr1, gata2, and id1, have been previously implicated in the regulation of HSCs. In situ hybridization in zebrafish kidney revealed that expression domains of egr1, gata2, and id1 overlapped with that of abcg2a, a marker for zSPs. These results suggest that the overlapping genes identified in this study are regulated in HSCs and play important roles in their functions.

CD10-positive mantle cell lymphoma: biologically distinct entity or an aberrant immunophenotype? Insight, through gene expression profile in a unique case series

2015 ◽  
Vol 68 (10) ◽  
pp. 844-848 ◽  
Author(s):  
Ariz Akhter ◽  
Etienne Mahe ◽  
Lesley Street ◽  
Payam Pournazari ◽  
Marco Perizzolo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mantle Cell Lymphoma ◽  
Gene Expression Profile ◽  
Expression Profile ◽  
Cell Lymphoma ◽  
Somatic Hypermutation ◽  
Case Series ◽  
Convincing Evidence ◽  
Minimal Impact ◽  
Mantle Cell

BackgroundMantle cell lymphoma (MCL) is an aggressive disease with genetic heterogeneity and discrete clinical subtypes. MCL is rarely CD10 positive. These cases raise the question whether a subset of MCL may be germinal centre (GC) derived, and have distinct clinicopathological characteristics.Aims and methodsA series of nine CD10-positive MCL cases is described herein. The clinicopathological and immunophenotypic features, immunoglobulin somatic hypermutation (SHM) status and gene expression profile (GEP) data are detailed. These features were compared with two independent sets (n=20, each) of CD10-negative MCL cases (controls), which were randomly selected from our institutional registry.ResultsGEP showed distinct expression of a GC signature in CD10-positive MCL cases with minimal impact on downstream signalling pathways. There were no significant differences in the clinicopathological features or clinical outcome between our CD10-positive and CD10-negative MCL cases. The frequency of SHM was comparable with established data.ConclusionsThis study provides convincing evidence that CD10 expression is related to a distinct GC signature in MCL cases, but without clinical or biological implications.

Farnesyltransferase Inhibitor Tipifarnib (Zarnestra) in Refractory Mantle Cell Lymphoma (MCL): A Therapeutic Target Only for Specific Patients Categorized by the 2-Gene Classifier for Predictive Response to Tipifarnib.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1561-1561
Author(s):  
Delphine Rolland ◽  
Vincent Ribrag ◽  
Corinne Haioun ◽  
Herve Ghesquieres ◽  
Fabrice Jardin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
Therapeutic Strategies ◽  
Prediction Of Response ◽  
Expression Ratio ◽  
Tumor Biopsy ◽  
Gene Expression Ratio ◽  
Mantle Cell ◽  
Initial Tumor

Abstract Background. Mantle cell lymphoma is one of the most refractory B-cell lymphomas. Despite the recent improvement of novel therapeutic strategies including high dose therapy and the introduction of immunotherapy, MCL patients are not cured by conventional therapeutic strategies. The increasing understanding of the MCL cell biology leads to the development of new drugs targeting to molecular mechanisms of the disease. Among the specific genes found to be overexpressed in MCL by gene expression profiling analysis, farnesyltransferase (FTase) encodes for an enzyme essential in the post- translational modifications of proteins that require prenylation for conversion to mature forms, allowing their participation in various signaling pathways regulating growth and survival. We recently demonstrated that inhibition of FTase by tipifarnib (Zarnestra) is associated in vitro with growth inhibition and apoptosis of MCL cell lines and in vivo with tumor xenograft stability. To determine the efficacy, the safety profile and the toxicity of tipifarnib in MCL, we conducted a phase II trial in patients with refractory MCL, and we evaluated the response considering published molecular predictors. Methods. Primary endpoint was the efficacy measured by the evaluation of the overall response rate (ORR) at 4 cycles, and, in case of response, at 6 cycles. Planned sample size of the study was 27 evaluable patients enrolled for an analysis based on an optimal two-stage design comprising 11 patients for the first stage and 16 for the second stage, under the hypothesis of an ORR of 35% to conclude for an effective drug and an ORR of 10% to conclude for an ineffective drug. Tipifarnib was administered at 300 mg orally twice daily for the first 21 days of each 28-days cycle for 4 to 6 cycles. Prediction of response was retrospectively evaluated in the initial tumor biopsy by the analysis of the 2-gene classifier, the RASGRP1/APTX gene expression ratio, and the AKAP13 expression level. Results. Eleven patients with refractory MCL were included in the analysis. Median number of lines of therapy before tipifarnib was 2.5 (range 1–7). Median age was 71 (range 66–79). All patients presented with stage IV disease and with good performance status. At 4 cycles of tipifarnib, 1 patient presented a complete response and 10 patients were in progressive disease. Two patients progressed during or after the first cycle, three patients after 3 cycles, and five patients after 4 cycles. No grade III-IV hematological toxicities were recorded. One patient presented an unrelated neurological symptom after the first dose administered. Evaluation of the molecular prediction of response to tipifarnib was realized for 3 patients: one responder patient and two non-responder patients. Results showed an increase in the RASGRP1/APTX gene expression ratio and a decrease in AKAP13 expression in the responder patient, and a decrease in the RASGRP1/APTX gene expression ratio and an increase in AKAP13 expression in the non-responder patients. This corresponds to the expected results of the response prediction to tipifarnib. Conclusion. Tipifarnib in refractory MCL was beneficial for only one patient. Response could be exactly predicted by specific molecular predictors of response evaluated in the initial tumor biopsy. These results demonstrate the necessity of categorizing molecularly the patients when targeted therapies are proposed to select those patients that might respond to.

Biology and Treatment of Mantle Cell Lymphoma in the Genomic Era.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. SCI-28-SCI-28
Author(s):  
Adrian Wiestner
Keyword(s):  
Gene Expression ◽  
Cyclin D1 ◽  
Mantle Cell Lymphoma ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
Cell Lymphoma ◽  
Genetic Alterations ◽  
Diagnostic Methods ◽  
Genetic Changes ◽  
Mantle Cell

Abstract Abstract SCI-28 The t11;14 translocation, the genetic hallmark of MCL, drives cyclin D1 expression in the tumor cells and historically facilitated the separation of MCL into a distinct entity. FISH cytogenetics are part of the workup and can be particularly helpful to separate leukemic MCL from CLL. Morphology and clinical course of MCL are heterogeneous and might have suggested the presence of different entities. Gene expression profiling answered this concern and provided several important insights: 1. despite the clinical heterogeneity, MCL has a characteristic gene expression profile supporting the accuracy of current diagnostic methods; 2. cyclin D1 negative MCL has the same diagnostic pathologic and gene expression features as cyclin D1 positive MCL, and 3. a gene expression based measure of tumor proliferation is a potent predictor of outcome and identifies patients with survival probabilities ranging from less than 1 year (highly proliferative tumors) to more than 6 years (low proliferation).1 Biologically, the gene expression based proliferation score integrates several acquired genetic changes in the tumor that include deletions of the INK4a/ARF locus encoding the tumor suppressors p14 and p16, amplification of BMI1, and secondary changes in the cyclin D1 locus. Mutations and deletions that alter the structure of the 3'UTR can enhance cyclin D1 mRNA stability,2 and the loss of miR binding sites in this region can enhance protein translation.3 These changes increase cyclin D1 protein resulting in increased proliferation. Additional genetic lesions such as deletions of ATM and p53 affect DNA damage responses pathways. The high frequency of secondary genetic changes in MCL cells may indicate genomic instability and the presence of additional chromosomal aberrations and certain genetic alterations hold prognostic information.4 With the continued refinement of whole genome genetic approaches the goal of identifying crucial pathways and possible driver genes in the pathogenesis of MCL may be within reach. MCL characterized by an antiapoptotic phenotype combined with features of aggressive lymphomas remains an incurable disease and having the worst outcome among all B-cell lymphomas. Biologic markers that predict treatment response and that could give way to targeted therapy have remained elusive. Several new drugs could help overcome treatment resistance and new analytic tools when incorporated into clinical trials may help dissect mechanisms of drug action and resistance. Our approach has been to incorporate gene expression profiling into a clinical trial of bortezomib to directly monitor the effects of the treatment on tumor biology in vivo. We identified an integrated stress response to bortezomib in sensitive tumors that may yield clinically usefully predictors of sensitivity and that could guide the development of improved therapies. 1. Rosenwald A, Wright G, Wiestner A, et al. The proliferation gene expression signature is a quantitative integrator of oncogenic events that predicts survival in mantle cell lymphoma. Cancer Cell. 2003;3:185-197. 2. Wiestner A, Tehrani M, Chiorazzi M, et al. Point mutations and genomic deletions in Cyclin D1 create stable truncated mRNAs that are associated with increased proliferation rate and shorter survival in mantle cell lymphoma. Blood. 2007. 3. Chen RW, Bemis LT, Amato CM, et al. Truncation in CCND1 mRNA alters miR-16-1 regulation in mantle cell lymphoma. Blood. 2008;112:822-829. 4. Salaverria I, Espinet B, Carrio A, et al. Multiple recurrent chromosomal breakpoints in mantle cell lymphoma revealed by a combination of molecular cytogenetic techniques. Genes Chromosomes Cancer. 2008;47:1086-1097. Disclosures Off Label Use: Bortezomib in previously untreated patients with MCL.

Bortezomib Is Effective for Down Regulation of Gene Transcriptions Specifically Expressed in Clonogenic Myeloma Side Population Cells

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3939-3939
Author(s):  
Miho Nara ◽  
Hiroyuki Tagawa ◽  
Kazuaki Teshima ◽  
Atsushi Watanabe ◽  
Mitsugu Ito ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cell ◽  
Cell Lines ◽  
Expression Analysis ◽  
Gene Expression Analysis ◽  
Kinase Inhibitor ◽  
Side Population ◽  
Aurora Kinase ◽  
Aurora Kinase B ◽  
Transporter Family

Abstract Abstract 3939 Background: Multiple myeloma (MM) is characterized by the accumulation of a population of malignant plasma cells within the bone marrow. Cytotoxic chemotherapy-based treatment is not curative, and the disease eventually recurs. Although currently available anti-MM strategies are effective at targeting the bulk of tumor cells, it is not clear that these agents are targeting the tumor-initiating subpopulation, or cancer stem cells. 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. SP cells express high levels of various members of the ABC transporter family, which are responsible for their drug resistance. A recent our work demonstrated that SP cells in MM have shown to exhibit stem cell like characteristics as well as high tumorigenicity. Therefore, it is worthy to identify gene/proteins specifically expressed in MM SP cells, which could be essential therapeutic targets. Purpose: The aim of this study was to identify genes and transcripts that could serve as molecular markers for targeting the MM SP cells, and to identify candidate agents for the MM SP cells. Experimental design: We used Hoechst 33342 dye to detect the MM SP in five MM cell lines (RPMI 8226, AMO1, KMS-12BM, KMS-11 and JJN3) and eight primary samples. We then tested whether the MM SP cells have stem-like characteristics and performed gene expression analysis to detect genes specifically expressed in the MM SP. On that basis, we tested candidate agents such as an aurora kinase inhibitor (VX-680), a histone methyltransferase inhibitor (DZNep), lenalidomide, thalidomide and a proteasome inhibitor (bortezomib) for their ability to target MM SP cells. Results: We found that clonogenic MM SP cells exhibit “stem cell-like” properties, including self renewal, differentiation and repopulation. Gene expression analysis of MM cell lines and primary samples revealed that, in SP cells, expression of genes related to G2/M phase (e.g. CDC2, CCNB1)-, microtubule attachment (e.g. BIRC5, CENPE, SKA1)-, mitosis or centrosomes (e.g. AURKB, KIF2C, KIF11, KIF15)-, proliferation (e.g. TOP2A, ASPM)-, polycomb (e.g. EZH2, EPC1)- and proteasomes(e.g. UBE2D3, UBE3C, PSMA5)- was significantly stronger in SP than non-SP cells. On that basis, we used VX-680, DZNep, lenalidomide, thalidomide and bortezomib against MM cells. Of these, bortezomib reduced the SP fraction most effectively due to its ability to reduce levels of target gene transcripts including phospho-histone H3, aurora kinase B and EZH2. Finally we tried to examine effects of those candidate agents to “clonogenic ability of SP”, and found that bortezomib possessed the most powerful effects for reduction of SP colonies. These results suggest that bortezomib has a broader range of targets than other agents and could include cell cycle, centrosome, polycomb and proteasome genes/proteins. Conclusion: Our findings are i) the first to identify genes specifically expressed in the MM SP, ii) the first to provide a rationale for treating MM using agents against genes and encoded proteins that are specifically expressed in MM SP cells. Disclosures: Iida: Janssen Pharmaceutical K.K.: Honoraria.

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