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  • 1
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    Correlation of Clinical and Molecular Response to Imatinib in Polycythemia Vera (PV) Patients with Bone Marrow Morphologic and Immunophenotypic Changes.
    American Society of Hematology ; 2006
    In:  Blood Vol. 108, No. 11 ( 2006-11-16), p. 4914-4914
    Details
    In: Blood, American Society of Hematology, Vol. 108, No. 11 ( 2006-11-16), p. 4914-4914
    Abstract: Imatinib, a tyrosine kinase inhibitor, is effective in treating erythrocytosis and splenomegaly in many PV patients (pts), but is less effective controlling thrombocytosis or splenomegaly in others. Imatinib in PV pts may inhibit c-kit signaling, essential for erythroid progenitor proliferation and/or PDGF-R signaling. The JAK2 V617F mutation is present in most PV pts. We found imatinib therapy in PV pts resulted in a modest molecular response based on %V617F that correlated with hematologic improvement/clinical response; however, those who achieved complete hematological remission had initially lower %V617F. Here we correlate bone marrow (BM) morphology and immunophenotype with clinical/molecular response to imatinib in 10 pts fulfilling criteria for PV (8 men, 2 women; 28–72 yr) treated with imatinib (400–800 mg/day) for 5–31 mo. Cytogenetics in 1 pt showed +9; 4 were normal. CR was defined as phlebotomy-free within18 mo. of treatment (Tx), HCT level & lt;45% for men/ & lt;42% for women, platelet count & lt;400×109/L and no splenomegaly. PR was similarly defined except the platelet count & gt; 400×109/L and & lt;50% reduction of palpable spleen size. %JAK2V617F was determined by pyrosequencing on pre-tx BM (5 pts) and post-tx PBL samples (all pts). Morphologic evaluation was done on sequential BM biopsies based on H & E/reticulin/trichrome stains and available BM aspirate smears. IHC was used to identify progenitors (CD34, CD117), megakaryocytes (MK; CD61), erythoid precursors (GlycoC), granulocytic precursors (MPO); MK c-mpl expression; proliferation (Ki-67). 2 pts showed CR, 6 PR and 2 NR. Median %V617F in CR was 15% (range 8–21%), in PR 57% (range 19–83%) and in NR 58% (range 44–72%). Both CR pts had 2–3-fold decrease in %V617F, whereas 3/6 PR pts had an increase (1–1.5 fold) in %V617F on tx. The 2 CR pts had in the pre-tx BM increased cellularity (60–80%), normal M:E ratio, moderate increase in MKs (10–15/20x). Imatinib tx resulted in normalization of cellularity, decreased erythropoiesis, a lesser decrease in granulopoiesis/megakaryopoiesis, and decreased proliferation in 1 pt (57% to 20%); the other the proliferation was stable at 24%. Reticulin fibrosis was minimal/mild. The PR/NR pre-tx BMs had markedly increased cellularity (80–100%), moderate/marked erythroid hyperplasia, increased granulopoiesis and moderate/marked increase in polymorphic MKs (10 to & gt;30/20x). Imatinib Tx resulted in decreased erythroid cells; less granulopoiesis; and no change/increased MKs with clustering and shedding of CD61+ platelets clumps into stroma. 2 cases progressed to fibrosis.The proliferation was variable (15–30%) with no change on Tx. C-mpl expression in MKs decreased with disease progression. The % cells expressing CD34 and/or CD117 was low and did not change. We found BM morphologic and immunophenotypic changes correlate with clinical/molecular response to imatinib in PV pts. Thus, BM evaluation may be helpful in assessing severity/disease progression and identifying pts who may benefit from imatinib Tx. The findings also suggest heterogeneity of hematopoietic stem cell proliferation. Targeting JAK2/other pathways involved in MK proliferation/migration may be beneficial in PV pts with large numbers of MKs who likely progress to fibrosis.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V108.11.4914.4914
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2006
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  • 2
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    Lymphoma Diagnosis and Plasma Epstein‐Barr Virus Load during Vicriviroc Therapy: Results of the AIDS Clinical Trials Group A5211
    Oxford University Press (OUP) ; 2009
    In:  Clinical Infectious Diseases Vol. 48, No. 5 ( 2009-03), p. 642-649
    Details
    In: Clinical Infectious Diseases, Oxford University Press (OUP), Vol. 48, No. 5 ( 2009-03), p. 642-649
    Type of Medium: Online Resource
    ISSN: 1058-4838 , 1537-6591
    URL: Issue
    URL: Article
    DOI: 10.1086/597768
    DOI: 10.1086/597007
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2009
    detail.hit.zdb_id: 2002229-3
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  • 3
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    Intensive Treatment Strategies May Not Provide Superior Outcomes in Mantle Cell Lymphoma: Overall Survival Exceeding Seven Years in a Large Cohort of Patients Managed Primarily with Conservative Therapies.
    American Society of Hematology ; 2007
    In:  Blood Vol. 110, No. 11 ( 2007-11-16), p. 1362-1362
    Details
    In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 1362-1362
    Abstract: Historically, reported outcomes in patients with mantle cell lymphoma (MCL) have been poor, with a median overall survival cited in the range of 2 to 4 years. As a consequence, recent approaches to first-line treatment have become more aggressive. Single- and oligo-center non-randomized studies with R-Hyper-CVAD and/or autologous stem cell transplant in first remission have produced 3-year overall survival 〉 80%, prompting many to consider them as optimal standard of care. However, a substantial fraction of MCL patients are ineligible to receive these regimens due to age and comorbidities. To determine whether these interesting results might be affected by patient referral/selection biases rather than a true superiority of therapy, we evaluated outcomes from our MCL patient cohort, a group potentially shaped by similar biases but largely managed in a more conservative fashion. As progression-free survival is likely improved by aggressive treatments, our focus is on overall survival given the central importance of this endpoint. Methods: We used pathology records to identify all patients with a diagnosis of MCL evaluated at the Weill Cornell Medical Center since 1997. Patients were considered eligible for inclusion if a date of diagnosis could be identified. In the subset where clinical records were limited, an online social security database was used to verify survival. Median overall survival was calculated according to the Kaplan-Meier method. Results: We identified 181 patients with the diagnosis of MCL established by standard hematopathologic criteria. Forty-eight of these cases were outside consults to our pathology department without available clinical data. Of the remaining 133 patients, date of diagnosis was identified in 111 subjects. Median age at diagnosis was 64 years (range: 37–88). For the subset of patients with available prognostic information, 81% were stage IV, 75% had bone marrow involvement, 52% had an IPI of ≥3. The median overall survival (N=111) was 7.1 years (85 months with 95% C.I. 63 to 98 mo.). Three-year overall survival was 86% (95% C.I. 78% to 92%). Adequate information on therapy was available for 75 patients. Most patients were treated with CHOP-like regimens. Only 5 were treated with (R)-Hyper-CVAD or autologous stem cell transplant in first remission while an additional 4 patients received one of these regimens as subsequent therapy, Five patients survived longer than 10 years—one patient is alive at 15.4 years—despite never receiving Hyper-CVAD or autoSCT. Univariate analysis of treatment type revealed no significant effect on overall survival. Conclusions: Our data demonstrate that single-center outcomes with conservative approaches in MCL can yield similar overall survival to that achieved with more intensive approaches at other single-centers. Therefore patient referral/selection biases may substantially account for the perceived superiority of aggressive strategies. Intensive treatment approaches for MCL should not be considered superior with respect to overall survival in the absence of long-term data from multicenter randomized trials comparing them to more conservative strategies.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V110.11.1362.1362
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2007
    detail.hit.zdb_id: 1468538-3
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  • 4
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    MicroRNA-Mediated Down-Regulation of the Tumor Suppressor Gene PRDM1/Blimp-1 in Diffuse Large B-Cell Lymphomas.
    American Society of Hematology ; 2007
    In:  Blood Vol. 110, No. 11 ( 2007-11-16), p. 3187-3187
    Details
    In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 3187-3187
    Abstract: PR (PRDI-BF1-RIZ-homology) domain zinc finger protein 1 (PRDM1) is a master regulator in plasma cell differentiation recently identified as a tumor suppressor target for inactivation in diffuse large B-cell lymphomas (DLBCL) of the activated B-cell (ABC) type, implying interference of B-cell terminal differentiation as a pathogenetic mechanism in DLBCL. Besides deleterious gene mutations, it has been suggested that PRDM1 may also be inactivated in DLBCL by an epigenetic mechanism. In this study, we examined the hypothesis of microRNA (miRNA)-mediated down-regulation of PRDM1 in DLBCL. 10 DLBCL cell lines and 25 clinical DLBCL samples were analyzed for PRDM1α (PRDM1 functional isoform) RNA and protein expression by quantitative real-time reverse transcriptase-PCR, Western blotting and immunohistochemistry. The clinical samples included 5 ABC-DLBCLs with PRDM1 gene deletions and inactivating mutations (Group I), 12 ABC-DLBCLs without PRDM1 mutations (Group II) and 8 germinal center B-cell (GCB) type (Group III). The myeloma cell line U266, which expresses relatively abundant PRDM1α mRNA and protein, was used as a reference standard (arbitrarily set as 1). These expression studies identify desynchrony in PRDM1α mRNA and protein expression. PRDM1α is weakly expressed or undetectable in DLBCL cell lines regardless of levels of PRDM1α transcripts. For the primary DLBCL cases, the mean levels of PRDM1α mRNA in groups I, II and III were: 2.21+0.53 (p 〈 0.05 vs. II & III), 0.84+0.19, and 0.43+0.24, respectively. However, immunohistochemistry demonstrated that in all three DLBCL groups, including Group II which has relatively high PRDM1α mRNA and harbors no PRDM1 mutations, an average of only 〈 5% (range: 0 to 10%) of the neoplastic B cells weakly expressed PRDM1. These results suggest epigenetic down-regulation of PRDM1 protein expression in some DLBCLs. Several lines of evidence support a role for miRNA let-7 in mediating translation repression of PRDM1 in DLBCLs: (1) let-7a levels in DLBCL cell lines and primary cases, as determined by quantitative modified Invader assays, are higher (∼2 to 30 fold) than in U266; (2) The lowest (let-7a)/(PRDM1α mRNA) ratio is found in those ABC-DLBCLs harboring PRDM1 mutations; (3) Enforced expression of let-7a caused binding site-dependent reduction in reporter gene activities of at least 50%. This reduction is due to translation repression; (4) Enforced let-7a expression reduces PRDM1α levels by ∼ 50% in U266 cell lines, suggesting functional in vivo interaction of let-7a with PRDM1 mRNA. In conclusion, PRDM1 protein levels correlate poorly with PRDM1 mRNA expression in DLBCLs. Our studies suggest miRNA-mediated down-regulation as a mechanism of lowering PRDM1 activity in DLBCL, apart from genetic mutations and transcription repression. In ABC-DLBCLs without PRDM1 gene mutations, PRDM1 inactivation is likely mediated at least in part via translation repression of PRDM1 transcripts by high levels of let-7. Those ABC-DLBCLs with PRDM1 gene mutations might have “escaped” let-7-mediated down-regulation, for example, via higher levels of induction of PRDM1 transcripts or some other mechanisms. let-7 may be considered a potential target for therapeutic inhibition to restore terminal differentiation in DLBCL cells.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V110.11.3187.3187
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2007
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 5
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    Decreased differentiation of erythroid cells exacerbates ineffective erythropoiesis in β-thalassemia
    American Society of Hematology ; 2008
    In:  Blood Vol. 112, No. 3 ( 2008-08-01), p. 875-885
    Details
    In: Blood, American Society of Hematology, Vol. 112, No. 3 ( 2008-08-01), p. 875-885
    Abstract: In β-thalassemia, the mechanism driving ineffective erythropoiesis (IE) is insufficiently understood. We analyzed mice affected by β-thalassemia and observed, unexpectedly, a relatively small increase in apoptosis of their erythroid cells compared with healthy mice. Therefore, we sought to determine whether IE could also be characterized by limited erythroid cell differentiation. In thalassemic mice, we observed that a greater than normal percentage of erythroid cells was in S-phase, exhibiting an erythroblast-like morphology. Thalassemic cells were associated with expression of cell cycle–promoting genes such as EpoR, Jak2, Cyclin-A, Cdk2, and Ki-67 and the antiapoptotic protein Bcl-XL. The cells also differentiated less than normal erythroid ones in vitro. To investigate whether Jak2 could be responsible for the limited cell differentiation, we administered a Jak2 inhibitor, TG101209, to healthy and thalassemic mice. Exposure to TG101209 dramatically decreased the spleen size but also affected anemia. Although our data do not exclude a role for apoptosis in IE, we propose that expansion of the erythroid pool followed by limited cell differentiation exacerbates IE in thalassemia. In addition, these results suggest that use of Jak2 inhibitors has the potential to profoundly change the management of this disorder.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2007-12-126938
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2008
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  • 6
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    Value of FDG-PET in Prediction of Splenectomy Findings in Patients with Suspected or Known Lymphoma.
    American Society of Hematology ; 2006
    In:  Blood Vol. 108, No. 11 ( 2006-11-01), p. 2405-2405
    Details
    In: Blood, American Society of Hematology, Vol. 108, No. 11 ( 2006-11-01), p. 2405-2405
    Abstract: Splenectomy is frequently performed for diagnostic purposes in patients with suspected or known lymphoma, including assessment for possible transformation. The ability to predict splenectomy findings (and potentially avoid associated morbidity and mortality) would be valuable. The purpose of this study was to determine whether preoperative18F-fluorodeoxyglucose positron emission tomography (FDG-PET) results correlate with pathologic diagnosis from splenectomy. Methods: One hundred sixty-five patients who had undergone a splenectomy at New York Presbyterian Hospital from January 2004 to July 2006 were identified from the pathology database. Records of these patients were searched and 11 with suspected or known lymphoma as an indication for splenectomy and who had a pre-splenectomy PET scan were identified. A nuclear medicine physician performed a blinded review and assigned each PET scan to one of the following categories based on splenic FDG standardized uptake values (SUV): low splenic metabolic activity (correlated with maximum SUV range 2-3.7), intermediate splenic metabolic activity (maximum SUV range 6–7), and high splenic metabolic activity (maximum SUV range 26–29). Findings were correlated with splenectomy pathologic diagnosis. Results: Subjects (n=11, 4 female, 7 male) had a median age of 48 years (range 21–72); four had suspected lymphoma pre-splenectomy, while 7 had a prior diagnosis and had splenectomy for diagnostic (to rule out transformation) or other purposes. Median time between PET and splenectomy was 1.25 months. Of 5 patients with low metabolic activity on PET; three had benign findings at splenectomy and two had splenic involvement of previously known mantle cell lymphoma. Three patients had intermediate metabolic activity on PET; all subsequently demonstrated marginal zone lymphoma at splenectomy. Three patients had high metabolic activity on PET; all were found to have diffuse large B cell lymphoma at splenectomy. Conclusions: This study to our knowledge comprises the largest series to evaluate splenic FDG-PET uptake in patients with suspected or known lymphoma, followed by subsequent pathologic confirmation. Patients with low splenic SUVs appear to be less likely to have splenic involvement of lymphoma, while intermediate and high values may correlate with lymphoma histology. Our findings support a potential role for FDG-PET as a tool for use, in conjunction with clinical and laboratory assessment, in consideration of the need for splenectomy in these settings.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V108.11.2405.2405
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2006
    detail.hit.zdb_id: 1468538-3
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  • 7
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    Neither Germinal Center (GC) vs Non-Germinal Center (Non-GC) Phenotype nor FOXP1 Expression Correlate with Outcome in AIDS-Associated Diffuse Large B-Cell Lymphoma (DLBCL): Study of Patients from AIDS Malignancies Consortium Trials 010 and 034.
    American Society of Hematology ; 2006
    In:  Blood Vol. 108, No. 11 ( 2006-11-01), p. 2023-2023
    Details
    In: Blood, American Society of Hematology, Vol. 108, No. 11 ( 2006-11-01), p. 2023-2023
    Abstract: Background: Germinal center (GC) and non-germinal center (non-GC) gene expression profiles correlate with survival in immunocompetent DLBCL patients. Phenotypic expression patterns of CD10, BCL6, MUM1 and CD138 are surrogates for genetic studies with comparable survival data; CD10+, BCL6+/−, MUM1- defines GC while CD10-, BCL6-, MUM1+/− identifies the non-GC phenotype with poorer prognosis. Expression of FOXP1, a transcription factor differentially expressed in resting and activated B cells, and PRDM1/BLIMP1, a regulator of terminal B cell differentiation, are also adverse prognostic markers for DLBCL in immunocompetent patients. AIDS-associated DLBCLs from uniformly treated HIV+ patients in AMC010 (CHOP vs. CHOP-rituxan) and AMC034 (EPOCH vs. EPOCH-rituxan) were examined to determine if the GC vs. non-GC phenotype, FOXP1 expression and/or BLIMP1 expression are prognostic in this patient population. Design: Slides of 32 and 30 AIDS-associated DLBCLs from AMC010 (closed) and AMC034 (in analysis) patients, respectively, were available for FOXP1, BLIMP1, CD10, BCL6, MUM1, BCL2, Ki-67 immunohistochemistry and in situ hybridization for EBV (EBER). Antigen expression by 〉 20% tumor cells ( 〉 10% for BLIMP1) was considered positive. GC phenotype was defined as CD10+, BCL6+/−, MUM1- while the non-GC cases were CD10-, BCL6-, MUM1+/−. Overall survival (OS) based on GC vs. non-GC phenotype was examined. FOXP1 expression was correlated with survival; BCL2, Ki-67 expression; and EBV status; BLIMP1 expression was correlated with survival in a subgroup of patients from AMC 034. Results: Of the 62 cases, 59% were MUM1, 60% BCL6, 53% CD10, 59% BCL2, 49% FOXP1, 67% BLIMP1 and 30% EBER positive. 19 (58%) cases were classified as GC and 14 as non-GC. No mean OS difference between GC and non-GC groups (p=0.74) or FOXP1+ and FOXP1- cases (p=0.8; t-test) in the AMC 010 patients; BLIMP1 expression did not correlate with survival in the subgroup of AMC 034 patients (p=0.4). GC vs. non-GC phenotype did not correlate with FOXP1 expression (p=0.1) or BLIMP1 expression (p=0.4). In addition, FOXP1 expression did not correlate with EBV positivity, BCL2, MUM1, BCL6 or CD10 expression or proliferation rate based on Ki67 (chi-square). Conclusions: AIDS-associated DLBCLs can be classified as GC and non-GC cases, but this classification does not appear to correlate with prognosis/OS in uniformly treated HIV-positive patients. Furthermore, in contrast with immunocompetent DLBCLs, FOXP1 expression also does not correlate with OS in this patient population; similarly BLIMP1 expression also does not correlate with survival in the HIV+ patient population. In addition, GC vs non-GC phenotype did not correlate with FOXP1 or BLIMP1 expression, while FOXP1 expression did not correlate with prognostic markers BCL2/Ki67 or EBV status. Thus, prognostic markers useful in immunocompetent patients with DLBCL may not be relevant for HIV positive patients, suggesting that patient immune status rather than tumor biology may be more important in predicting patient outcome.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V108.11.2023.2023
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2006
    detail.hit.zdb_id: 1468538-3
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  • 8
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    Mucosal Epithelial Cells Initiate Frontline Immunoglobulin Class Switching through an SLPI-Regulated Pathway.
    American Society of Hematology ; 2006
    In:  Blood Vol. 108, No. 11 ( 2006-11-16), p. 3898-3898
    Details
    In: Blood, American Society of Hematology, Vol. 108, No. 11 ( 2006-11-16), p. 3898-3898
    Abstract: Introduction. Class switching from IgM to IgG and IgA is central to immunity against microbes and usually occurs in draining lymph nodes and requires activation of B cells by CD4+ T cells expressing CD40 ligand. Growing evidence indicates that B cells can mount frontline IgG and IgA responses at mucosal sites of entry through an alternative CD40-independent pathway involving B cell-activating factor of the TNF family (BAFF, also known as BLyS) and a proliferation-inducing ligand (APRIL). These innate factors are usually produced by dendritic cells and stimulate B cells through at least three distinct receptors. Together with dendritic cells, epithelial cells have a key position at the host-environment interface. Therefore, we asked whether epithelial cells play a role in frontline antibody production. Methods. Tonsillar tissue sections from healthy donors were analyzed for expression of activation-induced cytidine deaminase (AID) by immunohistochemistry and in situ hybridization. A simplified in vitro model reproducing the geometry of mucosal surfaces was used to evaluate the role of epithelial cells in class switching. Briefly, primary epithelial cells and B cells were cultured in the upper and lower chambers, respectively, of a trans-well system. Monocyte-derived dendritic cells were positioned on a filter separating the two chambers. Various microbial product analogues were used to mimic infection. RNA interference was performed to knockdown BAFF in epithelial cells. AID expression, CSR, antibody production and signaling were evaluated in B cells as reported (Litinsky et al., Nat. Immunol.2002, 3:822–829; Qiao et al., Nat. Immunol.2006, 7:302–310). Results. We found that the upper respiratory mucosa of healthy subjects comprised intraepithelial pockets filled with B cells expressing AID, a DNA-editing enzyme associated with ongoing class switch DNA recombination (CSR). Epithelial cells released innate class switch-inducing factors, including BAFF, after sensing microbial products through TLRs, thereby inducing AID expression, CSR, and ultimately IgG and IgA production in neighboring B cells. Epithelial cell-induced antibodies comprised polyreactive IgG and IgA capable of recognizing multiple microbial determinants. Intraepithelial class switching was enhanced by thymic stromal lymphopoietin (TSLP), an epithelial IL-7-like cytokine that augments the innate B cell-licensing functions of dendritic cells, and restrained by secretory leukocyte protease inhibitor (SLPI), an epithelial alarm antiprotease that suppresses AID expression in activated B cells. Conclusions. The present findings indicate that epithelial cells function as non-immune sentinels capable to autonomously orchestrate compartmentalized IgG and IgA responses at the interface between host and environment. This implies that mucosal vaccines should activate both epithelial and immune cells to elicit optimal antibody production.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V108.11.3898.3898
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2006
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  • 9
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    Selective Inhibition of CDK4 and CDK6 Primes Chemoresistant MCL Cells for Killing by Proteasome Inhibitor Bortezomib by Activating Cell Cycle-Coupled Apoptosis
    American Society of Hematology ; 2008
    In:  Blood Vol. 112, No. 11 ( 2008-11-16), p. 3624-3624
    Details
    In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 3624-3624
    Abstract: Mantle Cell Lymphoma (MCL) remains generally incurable, suggesting that more effective control of unrestrained tumor growth is essential. Loss of cell cycle control is a hallmark of cancer, in particular of MCL where cell cycle progression through G1 is accelerated due to elevation of cyclin-dependent kinase 4 (CDK4) and constitutive cyclin D1 expression. Thus, one rational approach to improve MCL therapy is to target CDK4/6 in combination with cytotoxic killing. Although success in targeting the cell cycle in cancer with broad-spectrum CDK inhibitors has been modest, PD 0332991, the only known CDK4/6-specific inhibitor with oral bioavailability, has been shown to selectively and potently inhibit CDK4/6 in MCL cells ex vivo. Additionally, in a proof-of-mechanism study in patients with recurrent MCL, we have found that PD 0332991 is well tolerated, and effective in inhibiting CDK4 and CDK6 and suppressing tumor growth in vivo. Of note, 50% of the patients (8/16) have achieved a stable disease for greater then 40 weeks (Leonard et al, abstract submitted to ASH 2008). These findings suggest that selective targeting of CDK4 and CDK6 with PD 0332991 is a promising therapy for MCL. To advance targeting of the cell cycle in cancer, we have developed two novel approaches to both inhibit tumor cell proliferation and activate cell cycle-coupled apoptosis in MCL. We show in primary MCL tumor cells and MCL cell lines by BrdU pulse labeling and DNA content analysis that selective inhibition of CDK4/6 with PD 0332991 leads to a complete G1 arrest, despite high level of c-Myc expression and extensive chromosomal abnormality. As PD 0332991 acts reversibly, removal of PD 0332991 immediately releases the G1 block and induces synchronous ( 〉 90%) G1-S cell cycle progression and S phase entry. This sensitizes chemoresistant MCL cells to killing by suboptimal doses of cytotoxic agents such as bortezomib, through activating cell cycle-coupled apoptosis during S phase entry. Synergistic killing of MCL cells by induction of cell cycle synchronization with PD 0332991 in combination with bortezomib is mediated by induction of mitochondrial membrane depolarization and activation of caspase-9. In a complementary study, we have demonstrated that selective targeting of CDK4 and CDK6 by PD 0332991 similarly primes chemoresistant primary myeloma cells for cytotoxic killing by activating cell cycle-coupled apoptosis, and induces synergistic tumor suppression in animal models. Selective targeting of CDK4 and CDK6 by PD 0332991 in combination with cytotoxic killing, therefore, represents a promising new strategy for cell cycle-based therapy for MCL and other hematopoietic malignancies.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V112.11.3624.3624
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2008
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  • 10
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    Mutually Exclusive Structural Alterations of BLIMP1 and BCL6 Contribute to the Pathogenesis of Activated B Cell Type Diffuse Large B Cell Lymphoma.
    American Society of Hematology ; 2009
    In:  Blood Vol. 114, No. 22 ( 2009-11-20), p. 445-445
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    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 445-445
    Abstract: Abstract 445 Diffuse large B-cell lymphoma (DLBCL), the most common type of B-cell non-Hodgkin lymphoma, is a heterogeneous disease comprising multiple biologically and clinically distinct subgroups, including germinal center B cell-like (GCB) and activated B cell-like (ABC) DLBCL. We have previously reported that the BLIMP1 gene, a master regulator of plasma cell differentiation normally expressed in a subset of germinal center (GC) B cells and in all plasma cells, is inactivated by truncating mutations in a fraction of ABC-DLBCL, but not in GCB-DLBCL (Pasqualucci et al, J Exp Med 2006). In addition, most ABC-DLBCL lack expression of the BLIMP1 protein despite the presence of IRF4, another key regulator of plasma cell differentiation known to be invariably co-expressed with BLIMP1 in normal B cells, thereby suggesting that additional genetic or epigenetic mechanisms may inactivate BLIMP1 in these tumors. Here we report the characterization of the full spectrum of genetic lesions affecting the BLIMP1 locus in DLBCL, as determined by genome-wide copy number analysis (Affymetrix SNP 6.0 array), fluorescence in situ hybridization, and direct sequencing of the entire BLIMP1 coding region in 158 primary biopsies, classified by gene expression profile analysis (51 ABC-DLBCL; 62 GCB-DLBCL; 11 unclassified) and/or by immunohistochemistry (24 non-GC and 10 GC-DLBCL). This analysis uncovered a total of 22 mutations, distributed in 21 cases and segregating with an activated DLBCL phenotype (13/51 ABC-, 3/11 unclassified and 5/24 non-GC-DLBCL, vs 0/71 GCB/GC-DLBCL). The vast majority of the mutations were represented by frameshift insertions/deletions (n=10), splice site mutations (n=7) and nonsense mutations (n=1) leading to severely truncated polypeptides that lack critical functional domains and have therefore lost their activity. Interestingly, in the remaining three cases, 4 missense mutations introduced amino acid changes that were documented to severely impair BLIMP1 function by either causing protein instability (n=3) or abrogating its ability to bind chromatin and repress its known target genes CIITA and ID3 (n=1). When transduced into the GCB-DLBCL cell line BJAB, the wild type, but not three of the BLIMP1 missense mutant constructs induced cell cycle arrest. Copy number analysis confirmed deletion of the second allele in 9/12 mutated ABC-DLBCL, and identified three additional cases harbouring biallelic loss of the gene, including a focal homozygous deletion of 274Kb, which encompasses the BLIMP1 gene but not the two proximal genes ATG5 and PREP. Thus, 31% (n=16/51) of ABC-DLBCL have inactivation of BLIMP1 due to mutations or biallelic deletions. Moreover, immunohistochemical analysis revealed the lack of Blimp1 protein expression in 90% (n=27/30) of IRF4+ ABC-DLBCL carrying normal BLIMP1 loci. Notably, ten of these samples (30%) were found to harbour chromosomal translocations affecting BCL6, a master regulator of the GC and a direct transcriptional repressor of BLIMP1, suggesting that deregulated BCL6 expression was responsible for the lack of BLIMP1 expression in these cases. With the exception of two cases, BCL6 translocations and BLIMP1 structural alterations were mutually exclusive. Collectively, these data identify a novel mechanism by which missense mutations of BLIMP1 can impair its function in human DLBCL, and demonstrate that the IRF4-BCL6-BLIMP1 pathway is inactivated by structural alterations in over half of ABC-DLBCLs, strongly suggesting that BLIMP1 inactivation and BCL6 translocations may represent alternative mechanisms contributing to the pathogenesis of this disease by blocking terminal B cell differentiation. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V114.22.445.445
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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