Gene Expression Distinguishes Burkitt Lymphoma from Other Aggressive Lymphomas and Identifies Patients Who Are Highly Curable with Intensive Chemotherapeutic Regimens.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 415-415 ◽  
Author(s):  
Sandeep S. Dave ◽  
K. Fu ◽  
G. Wright ◽  
Lloyd Lam ◽  
T. C. Greiner ◽  
...  
Keyword(s):  
Gene Expression ◽  
Burkitt Lymphoma ◽  
Target Genes ◽  
Molecular Subtype ◽  
Performance Status ◽  
B Cell Lymphoma ◽  
Aggressive Lymphoma ◽  
Molecular Characteristics ◽  
Fish Analysis ◽  
Stem Cell Rescue

Abstract Background Burkitt lymphoma(BL) is a potentially curable, aggressive lymphoma. The distinction between BL and diffuse large B-cell lymphoma (DLBCL) is important because they differ significantly in clinical management. The distinction can be difficult because DLBCL can resemble BL in morphology, immunophenotype and cytogenetics. We investigated whether gene expression profiling (GEP) could create a molecular definition of BL that can reliably distinguish it from DLBCL. Methods Biopsy samples were collected from 312 patients with a diagnosis of sporadic BL or Burkitt-like lymphoma, or DLBCL. All cases were reviewed by a panel of expert hematopathologists. GEP of all the samples was carried out using a specialized oligonucleotide microarray. We constructed a predictor using 197 genes to distinguish BL from each molecular subtype of DLBCL. Leave-one-out cross-validation was used to evaluate the predictor’s performance. Chemotherapy treatments were grouped into either CHOP-like(CHOP, CNOP) or intensive(BFM, CODOX-M IVAC, regimens requiring stem cell rescue). Results After pathology review, the samples were reclassified as:classic BL(25 cases), atypical BL(19), DLBCL(261), and unclassifiable lymphoma(7). All classic BL and 18/19 cases of atypical BL shared a profile that was strikingly different from that of all the molecular subtypes of DLBCL, including those DLBCL cases that have a c-myc translocation. C-myc and its target genes, and genes related to germinal center differentiation were expressed at high levels in BL. NF-kB and its target genes and MHC class-I genes were expressed at very low levels in BL. Interestingly, 10 cases that were DLBCL by pathology were classified as BL by the predictor. The diagnosis of BL was supported by FISH analysis indicating a c-myc translocation. Among adults identified as having BL by the predictor (with full clinical data in N=15), overall survival was markedly superior for those receiving intensive regimens compared to CHOP-like regimens(Fig 1). The groups were similar with regard to age, stage, performance status and sites of involvement. Conclusion This study demonstrates that the molecular characteristics of BL can be used to accurately distinguish it from DLBCL. Importantly, a subgroup of BL was identified by the predictor that could not be diagnosed as BL by conventional criteria. The ability of the predictor to identify patients who benefit from aggressive therapies suggests that it will be useful in the diagnosis and management of patients with Burkitt lymphoma. Figure Figure

scholarly journals Reliable cell and tissue morphology-based diagnosis of endemic Burkitt lymphoma in resource-constrained settings in Ghana

2019 ◽  
Author(s):  
Cecilia Smith-Togobo ◽  
Mette Ø Pedersen ◽  
Steffen G Jensen ◽  
Babatunde Duduyemi ◽  
Richard K Gyasi ◽  
...  
Keyword(s):  
Burkitt Lymphoma ◽  
In Situ Hybridisation ◽  
B Cell Lymphoma ◽  
Diagnostic Tools ◽  
Fish Analysis ◽  
Fluorescence In Situ Hybridisation ◽  
Morphological Examination ◽  
Pathology Laboratory ◽  
Retrospective Assessment ◽  
Laboratory Investigations

Abstract Endemic Burkitt lymphoma (eBL) is an aggressive B-cell lymphoma, which is a common childhood cancer in areas with intense transmission of Plasmodium falciparum parasites. Early and accurate diagnosis is a prerequisite for successful therapy, but it optimally involves advanced laboratory investigations. These are technologically demanding, expensive, and often difficult to implement in settings where eBL is prevalent. Diagnosis is thus generally based on clinical assessment and morphological examination of tumour biopsies or fine-needle aspirates (FNAs). The purpose of the present study was to assess the accuracy of eBL diagnosis at two tertiary hospitals in Ghana. To that end, we studied FNAs from 29 eBL patients and 21 non-eBL lymphoma patients originally diagnosed in 2018. In addition, we examined 111 archival formalin-fixed and paraffin-embedded (FFPE) biopsies from Ghanaian patients originally diagnosed as eBL (N=55) or non-eBL (N=56) between 2010 and 2017. Availability-based subsets of samples were subjected to haematoxylin-eosin or Giemsa staining, C-MYC immunohistochemistry, and fluorescence in situ hybridisation (FISH) analysis of c-myc rearrangements We found a good correlation between original diagnosis and subsequent retrospective assessment, particularly for FNA samples. However, evidence of intact c-myc genes and normal C-MYC expression in samples from some patients originally diagnosed as eBL indicates that morphological assessment alone can lead to eBL over-diagnosis in our study area. In addition, several FFPE samples could not be assessed retrospectively, due to poor sample quality. Therefore, the simpler FNA method of obtaining tumour material is preferable, particularly when careful processing of biopsy specimens cannot be guaranteed. We conclude that the accuracy of eBL diagnostic tools available in Ghana is generally adequate, but could be improved by implementation of additional pathology laboratory investigations. Improved attention to adequate preservation of archival samples is recommended.

Molecular Profiling of Extramedullary and Medullary Plasmacytomas.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1806-1806 ◽  
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.

scholarly journals Genomic and transcriptomic characterization of heterogeneous immune subgroups of microsatellite instability-high colorectal cancers

2021 ◽  
Vol 9 (12) ◽  
pp. e003414
Author(s):  
Jung Ho Kim ◽  
Mi-Kyoung Seo ◽  
Ji Ae Lee ◽  
Seung-Yeon Yoo ◽  
Hyeon Jeong Oh ◽  
...  
Keyword(s):  
Gene Expression ◽  
Microsatellite Instability ◽  
Molecular Subtype ◽  
Colorectal Cancers ◽  
Molecular Characteristics ◽  
Immune Parameters ◽  
Whole Exome ◽  
Tumor Mutational Burden ◽  
Consensus Molecular Subtype

BackgroundColorectal cancers (CRCs) with microsatellite instability-high (MSI-H) are hypermutated tumors and are generally regarded as immunogenic. However, their heterogeneous immune responses and underlying molecular characteristics remain largely unexplained.MethodsWe conducted a retrospective analysis of 73 primary MSI-H CRC tissues to characterize heterogeneous immune subgroups. Based on combined tumor-infiltrating lymphocyte (TIL) immunoscore and tertiary lymphoid structure (TLS) activity, MSI-H CRCs were classified into immune-high, immune-intermediate, and immune-low subgroups. Of these, the immune-high and immune-low subgroups were further analyzed using whole-exome and transcriptome sequencing.ResultsWe found considerable variations in immune parameters between MSI-H CRCs, and immune subgrouping of MSI-H CRCs was performed accordingly. The TIL densities and TLS activities of immune-low MSI-H CRCs were comparable to those of an immune-low or immune-intermediate subgroup of microsatellite-stable CRCs. There were remarkable differences between immune-high and immune-low MSI-H CRCs, including their pathological features (medullary vs mucinous), genomic alterations (tyrosine kinase fusions vs KRAS mutations), and activated signaling pathways (immune-related vs Wnt and Notch signaling), whereas no significant differences were found in tumor mutational burden (TMB) and neoantigen load. The immune-low MSI-H CRCs were subdivided by the consensus molecular subtype (CMS1 vs CMS3) with different gene expression signatures (mesenchymal/stem-like vs epithelial/goblet-like), suggesting distinct immune evasion mechanisms. Angiogenesis and CD200 were identified as potential therapeutic targets in immune-low CMS1 and CMS3 MSI-H CRCs, respectively.ConclusionsMSI-H CRCs are immunologically heterogeneous, regardless of TMB. The unusual immune-low MSI-H CRCs are characterized by mucinous histology, KRAS mutations, and Wnt/Notch activation, and can be further divided into distinct gene expression subtypes, including CMS4-like CMS1 and CMS3. Our data provide novel insights into precise immunotherapeutic strategies for subtypes of MSI-H tumors.

scholarly journals Baseline Suvmax Did Not Predict Histological Transformation from Follicular Lymphoma to Aggressive Lymphoma in the Phase III GALLIUM Study

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4160-4160 ◽  
Author(s):  
Farheen Mir ◽  
Sally F Barrington ◽  
Michel Meignan ◽  
Helen Brown ◽  
Tina Nielsen ◽  
...  
Keyword(s):  
High Risk ◽  
Follicular Lymphoma ◽  
Research Funding ◽  
Performance Status ◽  
Bone Marrow Involvement ◽  
International Prognostic Index ◽  
B Cell Lymphoma ◽  
Phase Iii ◽  
Aggressive Lymphoma ◽  
Histological Transformation

Abstract Introduction: Follicular lymphoma (FL) generally has an indolent clinical course, but there is a 1-2% annual rate of histological transformation (HT) into aggressive lymphoma. Nodal HT sites have a higher maximum standardized uptake value (SUVmax) than non-transformed sites, and patients with HT typically show greater variation in SUVmax between sites. Upfront identification of patients at high risk of HT would allow physicians to consider treatment intensification. The objective of this analysis was to assess the relationship between baseline SUVmax (bSUVmax) and HT in the GALLIUM study (NCT01332968). Methods In the randomized, phase III GALLIUM study, 1202 previously untreated patients with grade 1-3a FL were randomized to receive induction with either obinutuzumab (GA101; G)- or rituximab (R)-based immunochemotherapy. Patients who responded received maintenance therapy with the same antibody. The primary endpoint of investigator-assessed progression-free survival was significantly improved in the G arm relative to the R arm (hazard ratio 0.66; p=0.001). As an exploratory endpoint, the degree of 18-fluorodeoxyglucose (FDG)-avidity expressed by SUVmax was assessed in patients with baseline FDG positron emission tomography (FDG-PET) scans by an independent review committee. Results: Among 522 patients with available bSUVmax data, 13 (2.5%) experienced biopsy-confirmed HT to diffuse large B-cell lymphoma or Grade 3b FL after a median follow-up of 59 months. Patients with HT were older (median age 61 vs 56 years), and were more likely to have a poor performance status (Eastern Cooperative Oncology Group [ECOG] performance status 2: 15.4% vs 2.6%), present with high-risk Follicular Lymphoma International Prognostic Index (FLIPI; 61.5% vs 40.3%), and have bone marrow involvement (76.9% vs 52.9%) than those without. More than 65% of patients showed bSUVmax >10, but only a minority of these experienced HT. Median (range) bSUVmax in patients with versus without HT was 12.4 (8.14, 27.95) versus 11.8 (3.05, 64.43), respectively. Median (range) baseline SUVrange (bSUVrange), defined as the difference between bSUVmax of the most and least FDG-avid lymphoma sites, was 6.6 (1.08, 23.91) versus 7.14 (0.00, 59.81), respectively (Figure). Conclusions: bSUVmax >10 is common in patients with previously untreated FL and is rarely associated with early HT. Neither bSUVmax nor bSUVrange predicted HT in GALLIUM, suggesting there may be little benefit in re-biopsy of lesions to exclude HT before commencing therapy. Better markers for identification of FL patients at risk of transformation are needed. Disclosures Mir: F. Hoffmann-La Roche: Employment. Barrington:F.Hoffmann-La Roche: Membership on an entity's Board of Directors or advisory committees; Department of Health (England): Research Funding; MRC: Research Funding; CRUK: Research Funding; EPSRC: Research Funding; National Institute of Health Research: Research Funding. Meignan:F. Hoffman-La Roche Ltd: Honoraria. Brown:PAREXEL, external business partner with Roche Products Ltd, Welwyn, UK: Employment. Nielsen:F. Hoffmann-La Roche Ltd: Employment, Other: Ownership interests PLC. Sahin:F. Hoffman-La Roche Ltd: Other: Ownership interests PLC. Trotman:F. Hoffman-La Roche: Other: Travel to meeting, Unremunerated member of Ad Board, Research Funding; Janssen: Other: Unremunerated member of Ad Board, Research Funding; Beigene: Research Funding; Takeda: Other: Unremunerated member of Ad Board; Celgene: Other: Unremunerated member of Ad Board, Research Funding; PCYC: Research Funding.

Efficacy and toxicity of dose-adjusted EPOCH-rituximab in adults with newly diagnosed Burkitt lymphoma

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 8035-8035 ◽  
Author(s):  
K. Dunleavy ◽  
B. R. Healey Bird ◽  
S. Pittaluga ◽  
N. Grant ◽  
M. Shovlin ◽  
...  
Keyword(s):  
Burkitt Lymphoma ◽  
Standard Therapy ◽  
Residual Disease ◽  
Tumor Lysis Syndrome ◽  
B Cell Lymphoma ◽  
Aggressive Lymphoma ◽  
Intrathecal Methotrexate ◽  
High Dose ◽  
Highly Effective ◽  
Hiv Negative

8035 Background: Burkitt Lymphoma (BL) is a rare and highly aggressive lymphoma, characterized by a high tumor proliferation rate. While the standard therapy of BL is highly effective, it involves intensive, multi-agent chemotherapy that is associated with considerable treatment-related toxicity and mortality, especially in older patients. We hypothesized that the regimen DA-EPOCH may be effective in BL, based on the observation that it overcomes the adverse effect of high proliferation in diffuse large B-cell lymphoma. Methods: We investigated DA-EPOCH-rituximab (R) in untreated BL in an attempt to maintain the high cure rates of standard therapy with minimal treatment related toxicity. Eligible patients had a diagnosis of untreated BL and could be HIV negative or positive with HIV negative patients (n=13) receiving 6 cycles of DA-EPOCH-R as previously described (Blood 99: 2685, 2002) and HIV positive (n=6) patients receiving 3–6 cycles of DA- EPOCH-R for 1 cycle beyond CR for a minimum of 3 cycles. All patients received intrathecal methotrexate prophylaxis and outpatient therapy where possible. Results: The characteristics of 19 enrolled patients are: median age (range) 29 (18–66) and ECOG PS 1(1–3); stage III/IV 10 (53%); LDH > N 11 (61%); male sex 15 (79%); extranodal sites 13 (68%) and ileocecal disease 13 (68%). No patients so far had CNS involvement at diagnosis. Response is CR/CRu in 100% of patients with one patient receiving consolidative radiotherapy to a site of residual disease. OS and PFS are both 100% and EFS 93.3% at a median potential follow-up time of 29 months. Toxicities were fever/neutropenia in 16%, grade 4 neutropenia in 47% and grade 3/4 thrombocytopenia in 22% of cycles. There was one case of tumor lysis syndrome and no treatment related deaths. Conclusions: DA-EPOCH-R is highly effective in BL. It appears to be associated with much lower toxicity compared to standard high-dose regimens and may significantly advance the therapeutic index of BL treatment. Accrual continues. No significant financial relationships to disclose.

Increased TCF-4 Expression Correlates with Reduced Caspase-3 Induction and Confers Resistance to Bortezomib.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 285-285
Author(s):  
Reshma Shringarpure ◽  
Deepak Bhole ◽  
Renate Burger ◽  
Laurence Catley ◽  
Klaus Podar ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Lines ◽  
Caspase 3 ◽  
Target Genes ◽  
Expression Patterns ◽  
B Cell Lymphoma ◽  
Initial Response ◽  
Cell Types ◽  
Differential Sensitivity ◽  
Bortezomib Treatment

Abstract Bortezomib (PS-341 / Velcade®) has achieved responses in the setting of relapsed refractory multiple myeloma, yet some patients either fail to respond or become refractory after an initial response. Moreover, despite the essential role of proteasomes in cell proliferation, not all tumor cell types respond to Bortezomib treatment. To define mechanisms for differential sensitivity to Bortezomib, we used gene expression profiling to compare global gene expression patterns in SUDHL-4 and SUDHL-6 B-cell lymphoma cell lines, which respond differentially to Bortezomib treatment. Of genes that were differentially expressed in the two cell lines, we chose to further examine differential expression of the transcription factor ‘T-cell factor 4′ (TCF-4), a downstream effector in Wnt signaling. TCF-4 expression was 15 fold higher in resistant SUDHL-4 cells compared to sensitive SUDHL-6 cells by microarray analysis, which was confirmed by real-time PCR. TCF-4 was constitutively associated with ß-catenin, its transcriptional co-activator, only in resistant SUDHL-4 cells, but not in sensitive SUDHL-6 cells. TCF-4 overexpression was associated with increased transcription of TCF-4 target genes cyclin D1 (3.48 fold) and c-myc (1.7 fold). Since all TCF-4 target genes are not defined, we also confirmed increased transcription by the TCF-4 / ß-catenin complex using TCF-4 / ß-catenin driven reporter genes. Increased TCF-4 expression in resistant SUDHL-4 cells was associated with lower induction of caspase-3 expression and activity in response to Bortezomib. Importantly, siRNA-mediated downregulation of TCF-4 sensitized cells to Bortezomib treatment, suggesting that blocking TCF-4 can restore sensitivity to Bortezomib-induced apoptosis. Our studies provide the rationale to use small molecule antagonists of TCF-4 / ß-catenin interaction to overcome Bortezomib resistance and improve patient outcome.

Interleukin-6–dependent gene expression profiles in multiple myeloma INA-6 cells reveal a Bcl-2 family–independent survival pathway closely associated with Stat3 activation

Blood ◽  
2004 ◽  
Vol 103 (1) ◽  
pp. 242-251 ◽  
Author(s):  
Katja Brocke-Heidrich ◽  
Antje K. Kretzschmar ◽  
Gabriele Pfeifer ◽  
Christian Henze ◽  
Dennis Löffler ◽  
...  
Keyword(s):  
Gene Expression ◽  
Signal Transduction ◽  
Multiple Myeloma ◽  
Interleukin 6 ◽  
Target Genes ◽  
B Lymphocyte ◽  
Expression Profiles ◽  
B Cell Lymphoma ◽  
Myeloma Cells ◽  
Survival Pathway

Abstract Interleukin 6 (IL-6) is a growth and survival factor for multiple myeloma cells. As we report here, the IL-6–dependent human myeloma cell line INA-6 responds with a remarkably rapid and complete apoptosis to cytokine withdrawal. Among the antiapoptotic members of the B-cell lymphoma-2 (Bcl-2) family of apoptosis regulators, only myeloid cell factor-1 (Mcl-1) was slightly induced by IL-6. Overexpression studies demonstrated, however, that IL-6 does not exert its survival effect primarily through this pathway. The IL-6 signal transduction pathways required for survival and the target genes controlled by them were analyzed by using mutated receptor chimeras. The activation of signal transducer and activator of transcription 3 (Stat3) turned out to be obligatory for the survival of INA-6 cells. The same held true for survival and growth of XG-1 myeloma cells. Gene expression profiling of INA-6 cells by using oligonucleotide microarrays revealed many novel IL-6 target genes, among them several genes coding for transcriptional regulators involved in B-lymphocyte differentiation as well as for growth factors and receptors potentially implicated in autocrine or paracrine growth control. Regulation of most IL-6 target genes required the activation of Stat3, underscoring its central role for IL-6 signal transduction. Taken together, our data provide evidence for the existence of an as yet unknown Stat3-dependent survival pathway in myeloma cells.

scholarly journals miR-17~92 Promotes Progression of ABC-DLBCL Lymphoma via Regulation of Canonical NF-kB Signaling

2021 ◽  
Author(s):  
Xianhuo Wang ◽  
Huaqing Wang ◽  
Xiaoyan Zhang ◽  
Chengfeng Bi ◽  
Timothy W. McKeithan ◽  
...  
Keyword(s):  
B Cell ◽  
Therapeutic Strategy ◽  
Target Gene ◽  
Target Genes ◽  
B Cell Lymphoma ◽  
Aggressive Lymphoma ◽  
Luciferase Reporter ◽  
Loss Of Function ◽  
Over Expression ◽  
Dual Luciferase Reporter Assay

Abstract Background: Activated B-cell like diffuse large B-cell lymphoma (ABC-DLBCL) is an aggressive lymphoma characterized by constitutive NF-κB activation. Nevertheless, the role and mechanisms of miR-17~92 in contributing to the NF-κB activation in ABC-DLBCL are still elusive. Methods: The expression of miR-17~92 primary transcript (MIR17HG) and NF-κB target genes was determined using RNA-sequencing. The expression of miR-17~92 was performed using microarray analysis. Plasmids carrying conditional over-expression and loss-of-function of miR-17~92 were respectively constructed and dual-luciferase reporter assay was used to validate the target gene of miR-17~92. Immunoprecipitation and polyubiquitination were further used to the study of potential mechanisms.Results: Expression of MIR17HG was positively correlated with NF-κB activity, miR-17~92 activated the NF-κB signaling in ABC-DLBCL, and its over-expression promoted ABC-DLBCL cell growth, accelerated cell G1 to S phase transition and enhanced cell resistance to NF-κB inhibitor. Importantly, miR-17~92 promoted NF-κB activation through directly targeting multiple ubiquitin-editing regulators to lead to increase the K63-linked polyubiquitination and decrease the K48-linked polyubiquitination of RIP1 complex in ABC-DLBCL. We further found that miR-17~92 selectively activated IκB-α and NF-κB p65 but not NF-κB p52/p100, and high miR-17~92 expression was also associated with poorer outcome in ABC-DLBCL patients. Conclusions: Taken together, miR-17~92 selectively activate the canonical NF-κB signaling via targeting ubiquitin-editing regulators to lead to constitutively NF-κB activation and poorer outcome, which is an innovative function of miR-17~92 and previously unappreciated regulatory mechanism of NF-κB activation in ABC-DLBCL. Targeting miR-17~92 may thus provide a novel bio-therapeutic strategy for ABC-DLBCL patients.

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