PB1855: LACK OF MUTATIONS IN TNFRSF13B (TACI) IN PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA
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ABSTRACT:
SUBMITTER: Giannakoulas N
PROVIDER: S-EPMC9430820 | biostudies-literature | 2022 Jun
REPOSITORIES: biostudies-literature
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Project description:TACI is a membrane receptor of BAFF and APRIL, contributing to the differentiation and survival of normal B cells. Although malignant B cells are also subjected on TACI signaling, there is a remarkable intradisease and interindividual variability of TACI expression in B-cell malignancies. The aim of our study was to explore the possible role of TACI signaling in the biology of chronic lymphocytic leukemia (CLL), including its phenotypic and clinical characteristics and prognosis. Ninety-four patients and 19 healthy controls were studied. CLL patients exhibited variable TACI expression, with the majority of cases displaying low to undetectable TACI, along with low to undetectable BAFF and increased APRIL serum levels compared to healthy controls. CLL cells with high TACI expression displayed a better survival capacity in vitro, when cultured with BAFF and/or APRIL. Moreover, TACI expression was positively correlated with the presence of monoclonal gammopathy and inversely with CD11c expression. Therefore, our study provides further evidence for the contribution of BAFF/APRIL signaling to CLL biology, suggesting also that TACI detection might be useful in the selection of patients for novel targeting therapeutic approaches.
| S-EPMC4408744 | biostudies-literature
Project description:BackgroundNOTCH1 PEST domain mutations in chronic lymphocytic leukemia have recently been shown to be of prognostic relevance. Both NOTCH1 and NOTCH2 are constitutively activated in B-cell CLL but not expressed in normal B cells and may be involved in survival and resistance to apoptosis in CLL. We screened for mutations in different parts of both NOTCH1 and NOTCH2 genes and related the changes to survival and other known risk factors.MethodsIn a cohort of 209 CLL patients, we used single strand conformation analysis to determine which of the samples carrying the NOTCH mutations and direct dideoxy sequencing was used to determine the exact nucleotide changes. Kaplan-Meier curves and log rank test were used to determine overall survival for NOTCH1 mutated cases and Cox regression analysis was used to calculate hazardous ratios.ResultsIn the present study, we found NOTCH1 PEST domain mutations in 6.7% of the cases. A shorter overall survival was found in patients with NOTCH1 mutations compared to wildtype (p = 0.049). Further, we also examined the extracellular and the heterodimerisation domains of the NOTCH1 gene and the PEST domain and heterodimerisation domain of the NOTCH2 gene, but no mutations were found in these regions. NOTCH1 mutations were most commonly observed in patients with unmutated IGHV gene (10/14), and associated with a more aggressive disease course. In addition, NOTCH1 mutations were almost mutually exclusive with TP53 mutations. In the combined group of NOTCH1 (6.7%) or TP53 (6.2%) mutations, a significant difference in overall survival compared to the wildtype NOTCH1 and TP53 was found (p = 0.002).ConclusionsBoth NOTCH1 and TP53 mutations seem to be independent predictive markers for worse outcome in CLL-patients and this study emphasizes the contention that NOTCH1 mutations is a novel risk marker.
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| S-EPMC10345848 | biostudies-literature
Project description:Although treatment options in breast cancer have been improved significantly, predictive biomarkers for disease progression and metastasis are still lacking. Recent studies indicate that several TNF Receptor Superfamily members are involved in breast cancer cell proliferation and survival. Interestingly, TNFRSF13B (TACI) mRNA level were of prognostic relevance in breast cancer patients. In this study we provide evidence for TACI expression on platelets of breast cancer patients. The level of platelet-expressed TACI (pTACI) was significantly increased on platelets derived from breast cancer patients compared to healthy controls. Upon platelet activation, pTACI was downregulated on the platelet surface of healthy donors and breast cancer patients. Of note, inhibition of matrix metalloprotease (MMP) prevented downregulation of pTACI ex vivo, indicating that proteolytic cleavage of pTACI is responsible for reduction of pTACI level. Stimulation of pTACI via BAFF, BAFF 60-mer or APRIL did not influence platelet activation and function. Remarkably, pTACI was particularly regulated during tumor progression in our breast cancer cohort. TACI expression levels on platelets were correlated with clinical parameters including tumor stage, occurrence of metastasis and tumor cell proliferation (Ki67). In conclusion, our data emphasize the potential use of platelets as a liquid biomarker in breast cancer.
| S-EPMC8010255 | biostudies-literature
Project description: Not available
| S-EPMC4140768 | biostudies-literature
Project description:We determined the immunoglobulin (Ig) V(H) subgroup expressed by the leukemia cells of 108 patients with B cell chronic lymphocytic leukemia (CLL). Surprisingly, we found that six samples (5%) each expressed Ig of more than one V(H) subgroup. Southern blot analysis demonstrated that these samples each had rearrangements involving both Ig heavy chain alleles. Nucleic acid sequence analyses of the Ig cDNA revealed each to express two functional Ig V(H) genes: V(H)3-33 and V(H)4-39; V(H)3-7 and V(H)4-39; V(H)3-23 and V(H)4-61; V(H)2-70 and V(H)3-30.3; or V(H)3-30 and V(H)4-b (DP67). One sample expressed three Ig V(H) genes: V(H)2-70, V(H)3-7, and V(H)4-59. Despite having more than one Ig heavy chain transcript, each sample was found to express only one functional Ig light chain. From the primary sequence, we deduced that the Ig of some of these CLL samples should react with Lc1, a monoclonal antibody (mAb) reactive with a supratypic cross-reactive idiotype present on Ig encoded by a subgroup of Ig V(H)4 genes (namely, V(H)4-39, V(H)4-b [DP-67], V(H)4-59, or V(H)4-61), and B6, an mAb that reacts with Ig encoded by certain Ig V(H)3 genes (namely, V(H)3-23, V(H)3-30, or V(H)3-30.3), and/or modified staphylococcal protein A (SpA), a 45-kilodalton bacterial "superantigen" that reacts with most Ig of the V(H)3 subgroup. Flow cytometric analyses revealed that such samples did in fact react with Lc1 and B6 and/or SpA, but not with control mAbs of irrelevant specificity. This study demonstrates that a subset of CLL patients have leukemic B cells that express more than one functional Ig heavy chain.
| S-EPMC2196272 | biostudies-literature
Project description:Chronic lymphocytic leukemia (CLL) is the most frequent leukemia type in which the genetic alterations influencing the clinico-biological course are not entirely understood. CLL has a heterogeneous course, with some patients showing an indolent course and others experiencing an aggressive course. Whole-genome sequencing and whole-exome sequencing studies identified recurrently mutated genes in CLL and profiled its clonal evolution patterns. However, more recent whole-genome sequencing studies also identified variants in non-coding sequences of the CLL genome, revealing important lesions outside the protein-coding regions. Here we describe the most representative non-coding lesion of the CLL genome, including lesions in the 3'-UTR region of NOTCH1 which result in the truncation of the NOTCH1 protein PEST domain, and non-coding mutations in an enhancer region on chromosome 9p13 which result in reduced expression of the PAX5 transcription factor. In addition, we describe the role of microRNA in CLL, in particular the miR15a/miR16-1 microRNA recurrently affected by deletions of chromosome 13q14. Together, new findings in non-coding genome genetic lesions provide a more complete portrait of the genomic landscape of CLL with clinical implications.
| S-EPMC6322188 | biostudies-other
Project description:Mutations in certain genes have been suggested to be associated with the pathogenesis of chronic lymphocytic leukemia (CLL), which is the most common leukemia in adults. In a case-control study, 100 patients with CLL and 105 healthy individuals were investigated for Notch homolog 1, translocation-associated (Drosophila) (NOTCH1) c.7544-7545delCT, recombinant splicing factor 3B subunit 1 (SF3B1) c.2098A>G, mouse double minute 2 homolog (MDM2) 40-bp insertion/deletion and myeloid differentiation primary response 88 (MYD88) L265P mutations by using allele specific-polymerase chain reaction (AS-PCR), a designed AS-PCR, PCR and PCR-restriction fragment length polymorphism methods, respectively. The presence of NOTCH1 and SF3B1 mutations were confirmed by genomic DNA sequencing. The NOTCH1 mutation was detected in 10% of patients and not detected in the control group. A higher frequency of NOTCH1 mutation was detected in patients with stage III CLL (62.5%) compared with stages 0-II CLL (37.5%) (odds ratio, 4.69-fold; 95% confidence interval, 1.0-21.9; P=0.049). The SF3B1 mutation was observed in 12% of the patients compared with 1.9% of the controls (P=0.012). The presence of MDM2 polymorphism was not associated with the risk or the stage of the disease. In addition, the MYD88 L265P mutation was not detected in the patients or the controls. The current study established the frequency of NOTCH1, SF3B1, MDM2 and MYD88 mutations in patients with CLL from the Kurdish population of Western Iran. In summary, a high frequency of NOTCH1 and SF3B1 mutations were identified in patients with CLL compared with healthy individuals, and the NOTCH1 mutation was associated with a high stage of the disease.
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Project description:TNFRSF13B/TACI defects have been associated with CVID pathogenesis and/or phenotype, especially the development of benign lymphoproliferation and autoimmunity. Our purpose was to investigate the role of TNFRSF13B/TACI defects in the pathogenesis of two common lymphoproliferative disorders, namely, sarcoidosis and tonsillar hypertrophy (TH). 105 patients (71 with sarcoidosis and 34 with TH, including 19 without infectious causative and 15 due to Haemophilus influenzae) were analyzed for TNFRSF13B/TACI defects. Two out of 19 TH patients without infectious cause (10.5%) and 2 patients with sarcoidosis (2.8%) displayed rare TNFRSF13B/TACI defects (I87N, L69TfsX12, E36L, and R202H, resp.). Both mutations identified in TH patients have been assessed as deleterious for protein function, while the patient with the R202H mutation and sarcoidosis exhibited also sIgG4D. Our study further supports the notion that TNFRSF13B/TACI defects alone do not result in CVID but may be also found frequently in distinct clinical phenotypes, including benign lymphoproliferation and IgG subclass deficiencies.
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