Low Level Amplification (Duplication) of 1q21 in Myeloma and Prognosis; the Role of CKS1B.

Abstract Introduction: Molecular cytogenetic studies have revealed that, to a great extent, the heterogeneity of myeloma is largely dictated by the underlying genetic and cytogenetic aberrations present in the clonal plasma cells. Most recently the group from the University of Arkansas identified strong prognostic associations with an increased level of gene expression of a cell cycle associated gene, CKS1B. CKS1B favors cell cycle progression by promoting degradation of p27 with release of the cyclin dependent kinases and entry into mitosis. Patients and methods: To further test this hypothesis we studied: a) via FISH for CKS1B amplification in a cohort of patients treated at the Mayo Clinic with high dose chemotherapy and stem cell support, as well as a group of patients with cytogenetically defined hypodiploidy, and b) a cohort of myeloma patients that were studied by gene expression profiling. Gene expression analysis was performed on CD138-enriched plasma-cell RNA using Affymetrix U133A chips (Affymetrix, Santa Clara, CA). Results: Of 159 patients studied 46 exhibited FISH abnormalities consistent with increase number of signals for CKS1B (30%): amplification was marginal or low in 44 cases, and in only two cases the ratio between CKS1B and control probe was greater than 2.0. Therefore, the predominant pattern is one of gene duplication rather than amplification where gene copy usually exceeds 10 and ratio with control probe exceeds 5 (e.g. HER-2/neu amplification). Patients with CKS1B duplication had a higher prevalence of chromosome 13 deletion (72%), and t(4;14) (29%). The presence of CKS1B duplication was more frequent (53%) among 19 patients with hypodiploidy. Using gene expression data for CKS1B, we found a positive association with t(14;16)(q32;q23). The level of CKS1B gene expression positively correlated with the PCLI (p<0.0001) but there was heterogeneity in this relationship (r2 = 0.34). We found no correlation between the expression level of CKS1B and p27 (r2 = 0.008, p = 0.37). While CKS1B gene duplication had a negative effect on survival this effect was weak (29.9 versus 38 months, p = 0.124. Median follow-up is 55 months) and disappeared when the variable was entered into the multivariate model including PCLI, B2-microglobulin and all the major genetic abnormalities by FISH. Likewise the level of expression of CKS1B determined by gene expression only carried prognostic significance when extreme levels of expression were utilized as a prognostic variable. Discussion: In this study we show that increase copy number of CKS1B is present in one third of patients with MM (majority of these being gene duplication) and seem to be associated with a shorter overall survival, but the net effect of this is rather weak in our series. Further study is needed to understand its potential role as a progression factor in the plasma cell neoplasms.

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Repurposing of KLF5 activates a cell cycle signature during the progression from a precursor state to oesophageal adenocarcinoma

eLife ◽

10.7554/elife.57189 ◽

2020 ◽

Vol 9 ◽

Author(s):

Connor Rogerson ◽

Samuel Ogden ◽

Edward Britton ◽

Yeng Ang ◽

Andrew D Sharrocks ◽

...

Keyword(s):

Gene Expression ◽

Cell Cycle ◽

Prognostic Significance ◽

Gene Expression Signature ◽

Chromatin Accessibility ◽

Oesophageal Adenocarcinoma ◽

Cell Cycle Gene ◽

Molecular Events ◽

Common Causes ◽

A Cell

Oesophageal adenocarcinoma (OAC) is one of the most common causes of cancer deaths. Barrett’s oesophagus (BO) is the only known precancerous precursor to OAC, but our understanding about the molecular events leading to OAC development is limited. Here, we have integrated gene expression and chromatin accessibility profiles of human biopsies and identified a strong cell cycle gene expression signature in OAC compared to BO. Through analysing associated chromatin accessibility changes, we have implicated the transcription factor KLF5 in the transition from BO to OAC. Importantly, we show that KLF5 expression is unchanged during this transition, but instead, KLF5 is redistributed across chromatin to directly regulate cell cycle genes specifically in OAC cells. This new KLF5 target gene programme has potential prognostic significance as high levels correlate with poorer patient survival. Thus, the repurposing of KLF5 for novel regulatory activity in OAC provides new insights into the mechanisms behind disease progression.

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Repurposing of KLF5 activates a cell cycle signature during the progression from a precursor state to Oesophageal Adenocarcinoma

10.1101/2020.02.10.941872 ◽

2020 ◽

Author(s):

Connor Rogerson ◽

Samuel Ogden ◽

Edward Britton ◽

Yeng Ang ◽

Andrew D. Sharrocks ◽

...

Keyword(s):

Gene Expression ◽

Cell Cycle ◽

Molecular Mechanisms ◽

Target Genes ◽

Prognostic Significance ◽

Gene Expression Signature ◽

Chromatin Accessibility ◽

Oesophageal Adenocarcinoma ◽

Cell Cycle Gene ◽

A Cell

AbstractOesophageal adenocarcinoma (OAC) is one of the most common causes of cancer deaths and yet compared to other common cancers, we know relatively little about the underlying molecular mechanisms. Barrett’s oesophagus (BO) is the only known precancerous precursor to OAC, but our understanding about the specific events leading to OAC development is limited. Here, we have integrated gene expression and chromatin accessibility profiles of human biopsies of BO and OAC and identified a strong cell cycle gene expression signature in OAC compared to BO. Through analysing associated chromatin accessibility changes, we have implicated the transcription factor KLF5 in the transition from BO to OAC. Importantly, we show that KLF5 expression is unchanged during this transition, but instead, KLF5 is redistributed across chromatin in OAC cells to directly regulate cell cycle genes specifically in OAC. Our findings have potential prognostic significance as the survival of patients with high expression of KLF5 target genes is significantly lower. We have provided new insights into the gene expression networks in OAC and the mechanisms behind progression to OAC, chiefly the repurposing of KLF5 for novel regulatory activity in OAC.

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Graft-versus-host disease and donor-directed hemagglutinin titers after ABO-mismatched related and unrelated marrow allografts: evidence for a graft-versus-plasma cell effect

Blood ◽

10.1182/blood.v96.3.1150 ◽

2000 ◽

Vol 96 (3) ◽

pp. 1150-1156 ◽

Cited By ~ 94

Author(s):

Marco Mielcarek ◽

Wendy Leisenring ◽

Beverly Torok-Storb ◽

Rainer Storb

Keyword(s):

Plasma Cell ◽

Graft Versus Host Disease ◽

Plasma Cells ◽

High Dose ◽

Hematopoietic Stem ◽

Host Disease ◽

Graft Versus Host ◽

Abo Incompatibility ◽

Transfusion Requirements ◽

Gradual Disappearance

Abstract The gradual disappearance of host antidonor isohemagglutinins after major ABO-mismatched hematopoietic stem cell (HSC) allografts has been attributed to the gradual destruction of host plasma cells by graft-versus-host effects. To corroborate this hypothesis, we retrospectively analyzed results from 383 major or major/minor ABO-mismatched unrelated and related HSC allografts performed between 1983 and 1998. All patients were conditioned by high-dose pretransplant therapy and given methotrexate/cyclosporine for graft-versus-host disease (GvHD) prophylaxis. Of the 383 patients, 155 had HLA-matched related and 228 had unrelated grafts. We asked whether unrelated recipients experienced a more rapid disappearance of isohemagglutinins than related recipients, and whether, within the groups of related and unrelated recipients, the titer disappeared faster in patients with GvHD than in those without GvHD. The median time to reach undetectable antidonor IgG and IgM titers was significantly shorter in unrelated recipients (46 versus 61 days; P = .016). In addition, related recipients with GvHD had a 2.2-fold increased likelihood (1.12-4.39,95% CI; P = .02) of reaching undetectable titers within 100 days than patients without GvHD. The persistence of antidonor isohemagglutinins led to significantly increased red blood cell (RBC) transfusion requirements in the ABO-mismatched related patients compared with ABO-matched counterparts. However, time to neutrophil and platelet engraftment, incidence of GvHD, and survival were not influenced by ABO incompatibility. In conclusion, our results corroborate the hypothesis that the rate of disappearance of antidonor isohemagglutinins after ABO-mismatched allogeneic HSC grafts is influenced by the degree of genetic disparity between donor and recipient, suggesting a graft-versus-plasma cell effect.

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Diffuse Large B-Cell Lymphoma: Risk Stratification and Management of Relapsed Disease

Hematology ◽

10.1182/asheducation-2005.1.252 ◽

2005 ◽

Vol 2005 (1) ◽

pp. 252-259 ◽

Cited By ~ 25

Author(s):

John W. Sweetenham

Keyword(s):

Gene Expression ◽

Risk Stratification ◽

B Cell ◽

International Prognostic Index ◽

Prognostic Significance ◽

Prognostic Index ◽

B Cell Lymphoma ◽

Molecular Techniques ◽

High Dose ◽

Large B Cell

Abstract The clinical factors described by the International Prognostic Index (IPI) provide a model for risk stratification in diffuse large B-cell lymphomas (DLBCLs). However, there is variability in outcome within IPI risk groups, indicating the biological and clinical heterogeneity of these diseases. Studies of gene expression profiling (GEP) in DLBCL are uncovering biological heterogeneity with prognostic significance. Various gene expression signatures with predictive value independent of the IPI are now recognized. Immunophenotypic features of DLBCL have also been shown to have prognostic value. The use of fluorodeoxyglucose–positron emission tomography (FDG-PET) scanning may provide additional predictive information when used at diagnosis or soon after initiation of treatment. Future prognostic models in DLBCL are likely to incorporate functional imaging, immunophenotype and GEPs as well as clinical data in risk stratification and choice of treatment. Treatment of relapsed DLBCL remains a major problem. High-dose therapy (HDT) and stem cell transplantation (SCT) has been shown to produce superior overall survival (OS) compared with conventional dose salvage therapy in patients with relapsed, chemosensitive DLBCL. However, only 20% to 30% of patients are cured by this approach, and the effectiveness of HDT and SCT in patients treated with rituximab-based combinations as first-line therapy is unknown. Although new transplant techniques including non-myeloablative allogeneic SCT are being investigated, their role is unclear. New treatment strategies are needed for these patients. The use of molecular techniques such as GEP is identifying many potential new therapeutic targets in DLBCL including histone deacetylase, HLA-DR, bcl-2, bcl-6, mTOR and TRAIL.

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The Human Plasma Cell Gene Expression Program.

Blood ◽

10.1182/blood.v104.11.3242.3242 ◽

2004 ◽

Vol 104 (11) ◽

pp. 3242-3242

Author(s):

John De Vos ◽

Dirk Hose ◽

Thierry Reme ◽

Hartmut Goldschmidt ◽

Jean-Francois Rossi ◽

...

Keyword(s):

Gene Expression ◽

Transcription Factors ◽

Cell Differentiation ◽

Plasma Cell ◽

Expression Profile ◽

Plasma Cells ◽

Plasma Cell Differentiation ◽

Unfolded Protein ◽

The Mean ◽

Protein Response

Abstract Seven purified peripheral blood memory B-cells (BM), seven in-vitro-generated polyclonal plasmablastic cells (PPC) and seven purified bone marrow mature plasma cells (BMPC) were studied by oligonucleotide microarrays. All samples were obtained from healthy volunteers. The gene expression profiling of these samples was determined with Affymetrix pan genomic U133A + B arrays (44 928 oligonucleotide probesets). We determined that 2313 genes were differentially expressed between these three B cell categories (P 〈 0.01 by a Kruskal-Wallis test and a ratio between two categories 〉 3). These 2313 genes were classified into six categories, according to the expression profile: early plasma cell genes (EPC), late plasma cell genes (LPC), genes lost early during plasma cell differentiation (LEPC), genes lost late during plasma cell differentiation (LLPC), genes upregulated only in plasmablasts (PBO) and genes lost only in plasmablasts (LPBO). As expected, Ig transcripts where essentially classified as EPC. As a corollary, genes involved in protein synthesis or degradation, transmembrane transporters and metabolism genes were overrepresented in EPC genes. Interestingly, genes involved in intercellular communication and extracellular matrix were enriched in LPC, highlighting the fact that mature plasma cells develop tight interactions with the bone marrow environment. Of note, genes involved in cell cycle are upregulated mainly in plasmablasts, whereas antiapoptotic genes are lost in plasmablasts only. Mains genes known to be involved in plasma cell differentiation display an expression profile in agreement with published data, as illustrated for transcription factors in Figure 1, validating this DNA microarray dataset. However most of these 2313 genes have either never been described yet or have no yet been linked to plasma cell differentiation. The description of those genes among our genome whose expression vary most during plasma cell differentiation will be an essential step in understanding the biology of a cell type essential to immune defenses and involved in deadly diseases. Figure 1: Transcription factors involved in plasma cell differentiation. Color indicates the expression profile category. For each gene is given the ratio of the mean expression value in plasma cell samples (PPC and BMPC) to the mean expression value in BM. UPR: Unfolded Protein Response. Figure 1:. Transcription factors involved in plasma cell differentiation. Color indicates the expression profile category. For each gene is given the ratio of the mean expression value in plasma cell samples (PPC and BMPC) to the mean expression value in BM. UPR: Unfolded Protein Response.

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Molecular Profiling of Extramedullary and Medullary Plasmacytomas.

Blood ◽

10.1182/blood.v114.22.1806.1806 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1806-1806 ◽

Cited By ~ 1

Author(s):

Anuj Mahindra ◽

Samir B Amin ◽

Gabriela Motyckova ◽

Aliyah R. Sohani ◽

Kishan Patel ◽

...

Keyword(s):

Gene Expression ◽

Plasma Cell ◽

Research Funding ◽

Plasma Cells ◽

Expression Patterns ◽

Tissue Microarrays ◽

Molecular Characteristics ◽

Fish Analysis ◽

New Therapeutic Approaches ◽

Risk Of Progression

Abstract Abstract 1806 Poster Board I-832 Plasmacytomas are rare clonal proliferations of plasma cells that though cytologically identical to plasma cell myeloma, present with osseous or extraosseous growth pattern. Understanding their molecular characteristics can provide crucial insights into their pathogenesis and risk of progression to multiple myeloma (MM). To investigate the differences between extramedullary (EMP) and medullary plasmacytomas (MP) and MM without plasmacytomas, we sought to molecularly profile these tumors by tissue microarrays, gene expression, microRNA, and FISH. We identified 85 patients from our data base with a pathological diagnosis of plasmacytoma. Of the 85 patients, 13 patients presented with EMP, and 72 had MP. Among the patients with EMP (n=13), 2 patients presented with multiple lesions. Three of 13 (23%) patients progressed to develop MM at a median of 12 months. 72 patients presented with MP, of which 21 had solitary lesions and 27 (37%) progressed to MM at a median of 20.5months. There was a male preponderance (67% vs 33%) and the median age at diagnosis was 60.5 years (range 27.7-87.6). The mean overall survival for patients with EMP was 121 months (95% confidence interval[CI] 97-144 months) and for patients with MP was 102 months (95% CI 93-128 months) { p=0.025} MicroRNA (miRNAs) profiling was performed on MP (n=19) and MM samples (n=66). Data was normalized using U6 endogenous control. Three hundred and one miRNAs out of a total 665 were significantly differentially expressed between MP vs MM samples. Gene expression profiling performed on MP will be correlated with the miRNA data to identify genes and transcripts of interest which will be functionally validated. Tissue microarrays were performed on 52 patients (8: EMP, 44: MP,) in whom paraffin-embedded tissue was available. Of samples analyzed, CD56 positivity was observed in 55% MP and 71% EMP samples (p=0.67). Additional staining for cyclin D1, Bcl 2 and FISH analysis will be reported. Differential expression patterns of factors involved in proliferation, survival, adhesion, and stroma-tumor cell interactions may help explain plasmacytoma biology and identify factors responsible for progression to MM. These insights may help identify new therapeutic approaches and targets in the treatment of these plasma cell disorders. Disclosures Hochberg: Enzon: Consultancy, Speakers Bureau; Biogen-Idec: Speakers Bureau; Genentech: Speakers Bureau; Amgen: Speakers Bureau. Anderson:Millennium: Research Funding. Raje:Celgene, Norvartis, Astrazeneca: Research Funding.

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Complete Response to First-Line Bortezomib-Thalidomide-Dexamethasone Therapy in Multiple Myeloma Patients with t(4;14): Analysis of Gene Expression Profile.

Blood ◽

10.1182/blood.v114.22.2811.2811 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2811-2811

Author(s):

Carolina Terragna ◽

Sandra Durante ◽

Daniel Remondini ◽

Giovanni Martinelli ◽

Francesca Patriarca ◽

...

Keyword(s):

Gene Expression ◽

Cell Cycle ◽

Multiple Myeloma ◽

Cell Cycle Progression ◽

Plasma Cells ◽

Expression Profiles ◽

First Line ◽

Cycle Progression ◽

Hedgehog Signalling ◽

Regulated Expression

Abstract Abstract 2811 Poster Board II-787 Introduction The recurrent translocation t(4;14)(p16;q32) occurs in less than 20% of patients with newly diagnosed Multiple Myeloma (MM) and is associated with a poor clinical outcome following either conventional or high-dose chemotherapy. Recently, it has been reported that patients carrying t(4;14) are prognostically heterogeneous and that the novel agents bortezomib and lenalidomide may overcome the poor prognosis related to this cytogenetic abnormality. In the present study, we analyzed the gene expression profile of patients who carried or not t(4;14) and were primarily treated with a bortezomib-based regimen. Patients and methods Two hundred thirty six patients with MM who received a combination of bortezomib-thalidomide-dexamethasone (VTD) as first-line therapy were evaluated for the presence at diagnosis of t(4;14). Of these, 41 patients (17.3%) were t(4;14) positive. On an intention-to-treat basis, the rate of CR and near CR (nCR) to VTD induction therapy among patients carrying t(4;14) was 41%, a value higher than the 29% observed among t(4;14) negative patients. In 218 patients for whom data on t(4;14), del(13q) and del(17p) were available, the differential gene expression of CD138+ enriched plasma cells was evaluated by means of expression microarray using the Affymetrix platform. The analysis was performed in t(4;14) negative patients and patients carrying t(4;14), either alone or combined with other abnormalities; t(4;14) negative patients included those with del(13q) alone and with any of these abnormalities. Results In 27 patients, t(4;14) was associated with either del(13q) (24 patients) or del(17p) (3 patients); the remaining 14 patients carried t(4;14) alone. The expression profiles of patients carrying either t(4;14) alone or t(4;14) combined with del(13q) significantly clustered apart when compared with those of cytogenetic negative patients. Similarly, the expression profiles of patients with del(13) alone clustered with those of cytogenetic negative patients. De-regulated expression of similar molecular pathways was demonstrated in patients carrying t(4;14) alone or combined with del(13q). Thus, the analysis of gene expression profiles according to response or no response to VTD was performed in two subgroups of patients, including those carrying t(4;14) alone or combined with del(13q) and those carrying either del(13q) alone or without cytogenetic abnormalities. By comparing the lists of genes differentially expressed (P '0.05) in patients who responded (e.g. those who achieved CR+nCR) and failed to respond (NR) to VTD according to the presence or absence of t(4;14), we found that the differential expression of 3719 genes characterized CR+nCR vs NR patients in the t(4;14) positive subgroup. At the opposite, the differential expression of 3182 genes characterized CR+nCR vs NR patients in the t(4;14) negative subgroup. 271 genes which were common to the two groups of genes were excluded from the list of genes found to be differentially expressed in t(4;14) positive patients who responded to VTD. Among these patients, we observed the de-regulated expression of genes involved in cell cycle progression (e.g. MDM2, CDK6 and SMAD2), Wnt signalling pathway (e.g. FZD7, WNT10A, MMP7,WNT2B, WNT6, WNT9A and DAAM2), and Hedgehog signalling pathway (GAS1, STK36 and GLI1). Overall, genes involved in cell cycle progression resulted over-expressed, thus suggesting a more aggressive phenotype of t(4;14) positive plasma cells of responder patients; nevertheless, the overall down-regulation of genes involved in Wnt and Hedgehog signalling pathways (known to be involved in the maintenance of a putative tumoral stem cell compartment) might mitigate this phenotype and predispose t(4;14) positive plasma cells to more favourably respond to VTD induction therapy. Supported by: BolognAIL, Fondazione Carisbo, Progetto di Ricerca Finalizzata (M.C). Disclosures: No relevant conflicts of interest to declare.

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Gene Expression Analysis Of Plasmablastic Lymphoma Identifies Down Regulation Of B Cell Receptor Signaling and Additional Unique Transcriptional Programs

Blood ◽

10.1182/blood.v122.21.3779.3779 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3779-3779 ◽

Cited By ~ 1

Author(s):

Jennifer R. Chapman-Fredricks ◽

Andrew J. Gentles ◽

Daxing Zhu ◽

Victoria Sujoy ◽

Izidore S Lossos

Keyword(s):

Gene Expression ◽

B Cell ◽

Plasma Cell ◽

Plasma Cells ◽

Expression Patterns ◽

Cell Receptor ◽

B Cell Receptor ◽

Receptor Signaling ◽

B Cell Receptor Signaling ◽

Cell Receptor Signaling

Abstract Plasmablastic lymphoma (PBL) is currently recognized as a distinct sub-type of diffuse large B-cell lymphoma (DLBCL), but remains a poorly characterized B-cell malignancy. We conducted gene expression profiling of 15 PBL, 10 DLBCL, and 5 EOP (extraosseous isolated plasmacytoma). 864 genes were significantly over- or under-expressed (at<1% false discovery rate) uniquely in one of these diseases relative to the other two. Of these, 102 were highly expressed in PBL relative to DLBCL and EOP, while 166 showed low expression in PBL. This set of 268 genes defined a distinct transcriptional program operating in PBL. Among these were surface markers such as CD320, CD300A, and IL6 receptor, as well as the cytokine Oncostatin M, which was highly expressed in PBL but almost never expressed in DLBCL or EOP. CD320 plays a role in generation and proliferation of plasma cells in the germinal center in response to IL-10 stimulation, while the immunoglobulin superfamily member CD300 is variably expressed across the hematopoietic hierarchy. The apoptosis-inducer BAX (Bcl-2 associated X protein) was highly expressed in PBL, similar to reports in plasma cell neoplasms. In addition the CpG methyltransferase gene Dnmt3b showed high expression levels in PBL. By comparing malignancy-specific gene expression patterns to known biological pathways, we found that expression of components of the B-cell receptor signaling pathway (Cd79a, Cd79b, Blk, Lyn, Syk, Ptprc, Csk, Pik3cd, Swap70, and Rel) were repressed by 2-fold or more on average in PBL relative to DLBCL. We observed a similar pattern in EOP relative to DLBCL. In contrast, mitochondrial genes were more highly expressed in PBL than in DLBCL. Analysis against a large compendium of sets of transcription factor targets from motif and ChIP analyses identified that targets of MYB, a major transcriptional regulator of hematopoietic differentiation, were up-regulated in PBL; whereas targets of NFKB1 were repressed relative to DLBCL. Both PBL and EOP highly expressed genes that have previously been described as up-regulated in plasmacytomas. To further investigate the potential cell of origin of these malignancies, we compared genes expressed in PBL, DLBCL, and EOP to genes that are highly expressed in specific sub-types of B-cells. Genes highly expressed in plasma cells relative to other types of B-cells were highly expressed in PBL and EOP compared to DLBCL. Notably, this included the transcription factor XBP1 (X-box binding protein 1), which is a critical regulator of plasma cell differentiation. The plasma cell marker CD138 (syndecan-1, encoded by the Sdc1 gene) was also over-expressed in the PBL and EOP samples. We have validated the array data by reanalyzing expression of four candidate genes (Lyn, Syk, SPIB, and Swap70) by real time PCR. These four genes were highly expressed in DLBCL, but their expression was low in both in PBL and EOP. The observed overexpression of Swap70 in DLBCL as compared to PBL and EOP was subsequently validated by immunohistochemistry (IHC). Immunostaining for Swap70 was performed in all 30 cases used for array analysis and was negative in all cases of PBL (0/15 positive) and EOP (0/5 positive) but was diffusely positive in all but one of the DLBCLs (9/10 positive). Swap70 analysis by IHC was subsequently performed in 7 additional cases of DLBCL and was diffusely positive in all of these cases (7/7), thus suggesting that immunohistochemical analysis for Swap70 may be useful in differentiating PBL and EOP from DLBCL. Overall our results provide insight into the unique transcriptional programs distinguishing PBL from morphologic and clinical mimics DLBCL and EOP, as well as identify similarities between them. Most notably, we observed that B-cell receptor signaling pathway genes are significantly down-regulated in PBL and EOP compared to DLBCL. These findings corroborate the downregulation of surface immunoglobulin expression as seen in PBL and EOP and suggest a biologic similarity between these two neoplasms. Among normal B-cell sub-populations, PBL and EOP were most similar in their expression patterns to plasma cells and plasmablasts in that they expressed several well-known plasma cell markers. These findings additionally identify novel candidate genes that provide opportunities for further phenotypic and functional characterization of these neoplasms. Disclosures: No relevant conflicts of interest to declare.

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Graft-versus-host disease and donor-directed hemagglutinin titers after ABO-mismatched related and unrelated marrow allografts: evidence for a graft-versus-plasma cell effect

Blood ◽

10.1182/blood.v96.3.1150.015k51_1150_1156 ◽

2000 ◽

Vol 96 (3) ◽

pp. 1150-1156 ◽

Cited By ~ 1

Author(s):

Marco Mielcarek ◽

Wendy Leisenring ◽

Beverly Torok-Storb ◽

Rainer Storb

Keyword(s):

Plasma Cell ◽

Graft Versus Host Disease ◽

Plasma Cells ◽

High Dose ◽

Hematopoietic Stem ◽

Host Disease ◽

Graft Versus Host ◽

Abo Incompatibility ◽

Transfusion Requirements ◽

Gradual Disappearance

The gradual disappearance of host antidonor isohemagglutinins after major ABO-mismatched hematopoietic stem cell (HSC) allografts has been attributed to the gradual destruction of host plasma cells by graft-versus-host effects. To corroborate this hypothesis, we retrospectively analyzed results from 383 major or major/minor ABO-mismatched unrelated and related HSC allografts performed between 1983 and 1998. All patients were conditioned by high-dose pretransplant therapy and given methotrexate/cyclosporine for graft-versus-host disease (GvHD) prophylaxis. Of the 383 patients, 155 had HLA-matched related and 228 had unrelated grafts. We asked whether unrelated recipients experienced a more rapid disappearance of isohemagglutinins than related recipients, and whether, within the groups of related and unrelated recipients, the titer disappeared faster in patients with GvHD than in those without GvHD. The median time to reach undetectable antidonor IgG and IgM titers was significantly shorter in unrelated recipients (46 versus 61 days; P = .016). In addition, related recipients with GvHD had a 2.2-fold increased likelihood (1.12-4.39,95% CI; P = .02) of reaching undetectable titers within 100 days than patients without GvHD. The persistence of antidonor isohemagglutinins led to significantly increased red blood cell (RBC) transfusion requirements in the ABO-mismatched related patients compared with ABO-matched counterparts. However, time to neutrophil and platelet engraftment, incidence of GvHD, and survival were not influenced by ABO incompatibility. In conclusion, our results corroborate the hypothesis that the rate of disappearance of antidonor isohemagglutinins after ABO-mismatched allogeneic HSC grafts is influenced by the degree of genetic disparity between donor and recipient, suggesting a graft-versus-plasma cell effect.

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Investigating the Central Dogma of Molecular Biology in the Context of Nuclear Architecture and Cell Cycle

10.1101/810499 ◽

2019 ◽

Author(s):

Shivnarayan Dhuppar ◽

Aprotim Mazumder

Keyword(s):

Gene Expression ◽

Cell Cycle ◽

Single Molecule ◽

Mammalian Cells ◽

Nuclear Architecture ◽

Nuclear Lamina ◽

Gene Copy ◽

A Cell ◽

Cycle Dependent

AbstractNuclear architecture is the organization of the genome within a cell nucleus with respect to different nuclear landmarks such as nuclear lamina, matrix or nucleoli. Lately it has emerged as a major regulator of gene expression in mammalian cells. The studies connecting nuclear architecture with gene expression are largely population-averaged and do not report on the heterogeneity in genome organization or in gene expression within a population. In this report we present a method for combining 3D DNA Fluorescence in situ Hybridization (FISH) with single molecule RNA FISH (smFISH) and immunofluorescence to study nuclear architecture-dependent gene regulation on a cell-by-cell basis. We further combine it with an imaging-based cell cycle staging to correlate nuclear architecture with gene expression across the cell cycle. We present this in the context of Cyclin A2 (CCNA2) gene for its known cell cycle-dependent expression. We show that, across the cell cycle, the expression of a CCNA2 gene copy is stochastic and depends neither on its sub-nuclear position—which usually lies close to nuclear lamina—nor on the expression from the other copies.

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