Promising Immunotherapeutic Modalities for B-Cell Lymphoproliferative Disorders.
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ABSTRACT:
SUBMITTER: Mihalyova J
PROVIDER: S-EPMC8584080 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundHuman B-cell responses are regulated through synergy between a collection of activation and inhibitory receptors. Fc receptor-like (FCRL) molecules have recently been identified as co-receptors that are preferentially expressed in human B-cells, which may also play an important role in the regulation of human B-cell responses. FCRL1 is a member of the FCRL family molecules with 2 immunoreceptor tyrosine-based activation motifs (ITAMs) in its cytoplasmic tail. This study aimed to investigate the regulatory roles of FCRL1 in human B-cell responses.Materials and methodsThe regulatory potential of FCRL1 in human B-cell through knockdown of FCRL1 expression in the Ramos and Daudi Burkitt lymphoma (BL) cell lines by using the retroviral-based short hairpin ribonucleic acid (shRNA) delivery method. The functional consequences of FCRL1 knockdown were assessed by measuring the proliferation, apoptosis, and the expression levels of Bcl-2, Bid, and Bax genes as well as phosphoinositide-3 kinase/-serine-threonine kinase AKT (PI3K/p-AKT) pathway in the BL cells, using the quantitative real-time polymerase chain reaction (PCR) and flow cytometry analysis. The NF-κB activity was also measured by the enzyme-linked immunosorbent assay (ELISA).ResultsFCRL1 knockdown significantly decreased cell proliferation and increased apoptotic cell death in the BL cells. There was a significant reduction in the extent of the Bcl-2 gene expression in the treated BL cells compared with control cells. On the contrary, FCRL1 knockdown increased the expression levels of Bid and Bax genes in the treated BL cells when compared with control cells. In addition, the extent of the PI3K/p-AKT expression and phosphorylated-p65 NF-κB activity was significantly decreased in the treated BL cells compared with control cells.ConclusionsThese results suggest that FCRL1 can play a key role in the activation of human B-cell responses and has the potential to serve as a target for immunotherapy of FCRL1 positive B-cell-related disorders.
| S-EPMC6864034 | biostudies-literature
Project description:This article highlights recent discoveries about Notch activation and its oncogenic functions in lymphoid malignancies, and discusses the therapeutic potential of Notch inhibition.NOTCH mutations arise in a broad spectrum of lymphoid malignancies and are increasingly scrutinized as putative therapeutic targets. In T-cell acute lymphoblastic leukemia (T-ALL), NOTCH1 mutations affect the extracellular negative regulatory region and lead to constitutive Notch activation, although mutated receptors remain sensitive to Notch ligands. Other NOTCH1 mutations in T-ALL and NOTCH1/2 mutations in multiple B-cell malignancies truncate the C-terminal proline (P), glutamic acid (E), serine (S), threonine (T)-rich (PEST) domain, leading to decreased Notch degradation after ligand-mediated activation. Thus, targeting Notch ligand-receptor interactions could provide therapeutic benefits. In addition, we discuss recent reports on clinical testing of Notch inhibitors in T-ALL that influenced contemporary thinking on the challenges of targeting Notch in cancer. We review advances in the laboratory to address these challenges in regards to drug targets, the Notch-driven metabolome, and the sophisticated protein-protein interactions at Notch-dependent superenhancers that underlie oncogenic Notch functions.Notch signaling is a recurrent oncogenic pathway in multiple T- and B-cell lymphoproliferative disorders. Understanding the complexity and consequences of Notch activation is critical to define optimal therapeutic strategies targeting the Notch pathway.
| S-EPMC4962559 | biostudies-literature
Project description:Cyclin-dependent protein kinase 6 (CDK6), in cooperation with cyclin Ds, drives cell cycle progression from G1 to S phase through phosphorylation and subsequent inactivation of retinoblastoma 1 protein. Alteration of this pathway results in both nonhematologic and hematologic malignancies, which include a small subset of B-cell lymphoproliferative disorders (BLPDs). We identified 5 cases of BLPD that carried CDK6 chromosomal translocations and characterized their clinical, pathologic, immunophenotypic, and genetic features. Common clinical characteristics included marked neoplastic lymphocytosis, systemic lymphadenopathy, splenomegaly, and bone marrow involvement. Three patients were diagnosed with low-grade B-cell lymphoma and had an indolent clinical course, and 2 patients (one who transformed to large B-cell lymphoma, and the other who was initially diagnosed with a high-grade B-cell lymphoma) had an aggressive clinical course. Immunophenotypically, the neoplastic B cells expressed CD5, CDK6, and cytoplasmic retinoblastoma 1 protein in all cases, expressed phospho-RB, p27kip1, and cyclin D2 in most cases, and uniformly lacked expression of all other cyclins. In 4 cases, the CDK6 translocation partner was kappa immunoglobulin light-chain gene; and in the fifth case, the CDK6 translocation partner was unknown. These distinct clinicopathologic and cytogenetic features distinguish the CDK6 translocation-associated BLPDs (CDK6-BLPDs) from other mature B-cell lymphomas.
| S-EPMC2674112 | biostudies-literature
Project description:Post-transplant lymphoproliferative disorders of T- or NK-cell origin (T/NK-PTLD) are rare entities and their genetic basis is unclear. We performed targeted sequencing of 465 cancer-related genes and high-resolution copy number analysis in 17 T-PTLD and 2 NK-PTLD cases. Overall, 377 variants were detected, with an average of 20 variants per case. Mutations of epigenetic modifier genes (TET2, KMT2C, KMT2D, DNMT3A, ARID1B, ARID2, KDM6B, n=11). and inactivation of TP53 by mutation and/or deletion(n=6) were the most frequent alterations, seen across disease subtypes, followed by mutations of JAK/STAT pathway genes (n=5). Novel variants, including mutations in TBX3 (n=3), MED12 (n=3) and MTOR (n=1), were observed as well. High-level microsatellite instability was seen in 1 of 14 (7%) cases, which had a heterozygous PMS2 mutation. Complex copy number changes were detected in 8 of 16 (50%) cases and disease subtype-specific aberrations were also identified. In contrast to B-cell PTLDs, the molecular and genomic alterations observed in T/NK-PTLD appear similar to those reported for peripheral T-cell lymphomas occurring in immunocompetent hosts, which may suggest common genetic mechanisms of lymphoma development.
| S-EPMC5122338 | biostudies-literature
Project description: Not available
| S-EPMC8252412 | biostudies-literature
Project description:Flavopiridol downmodulates antiapoptotic proteins associated with resistance to fludarabine and rituximab and is effective against p53-mutated chronic lymphocytic leukemia (CLL). We conducted a phase I study of flavopiridol, fludarabine, and rituximab (FFR) in patients with mantle-cell lymphoma (MCL), indolent B-cell non-Hodgkin's lymphomas (B-NHL), and CLL to determine the activity of FFR.Therapy included fludarabine 25 mg/m(2) intravenously (IV) days 1 to 5 and rituximab 375 mg/m(2) day 1 every 28 days for 6 cycles. We administered flavopiridol 50 mg/m(2) by 1-hour IV bolus (IVB) day 1 (n = 15); day 1 to 2 (n = 6); 20 mg/m(2) 30-minute IVB + 20 mg/m(2) 4-hour IV infusion (n = 3); or 30 mg/m(2) + 30 mg/m(2) (n = 14).Thirty-eight patients (median age, 62 years) with MCL (n = 10); indolent B-NHL including follicular (n = 9), marginal zone (n = 4), lymphoplasmacytic (n = 1), or small lymphocytic lymphoma (n = 3); and CLL (n = 11), were enrolled. Twenty-two patients were previously untreated; 16 had received one to two prior therapies. Two patients in cohort 2 developed grade 3 dose-limiting toxicity (seizures, renal insufficiency). The median number of treatment cycles was 4, with cytopenias (n = 10) and fatigue (n = 3) the most common reasons for early discontinuation. Overall response rate was 82% (complete response, 50%; unconfirmed complete response, 5%; partial response, 26%), including 80% of patients with MCL (median age, 68; seven complete responses, one partial response). Median progression-free survival (PFS) was 25.6 months. Median PFS of patients with nonblastoid variant MCL (n = 8) was 35.9 months.FFR was active in MCL, indolent B-NHL, and CLL and should be studied for older patients with MCL who are not candidates for aggressive chemotherapy.
| S-EPMC2815704 | biostudies-literature
Project description:The intestinal immune system, which must ensure appropriate immune responses to both pathogens and commensal microflora, comprises innate lymphoid cells and various T-cell subsets, including intra-epithelial lymphocytes (IELs). An example of innate lymphoid cells is natural killer cells, which may be classified into tissue-resident, CD56bright NK-cells that serve a regulatory function and more mature, circulating CD56dim NK-cells with effector cytolytic properties. CD56bright NK-cells in the gastrointestinal tract give rise to indolent NK-cell enteropathy and lymphomatoid gastropathy, as well as the aggressive extranodal NK/T cell lymphoma, the latter following activation by EBV infection and neoplastic transformation. Conventional CD4+ TCRαβ+ and CD8αβ+ TCRαβ+ T-cells are located in the lamina propria and the intraepithelial compartment of intestinal mucosa as type 'a' IELs. They are the putative cells of origin for CD4+ and CD8+ indolent T-cell lymphoproliferative disorders of the gastrointestinal tract and intestinal T-cell lymphoma, NOS. In addition to such conventional T-cells, there are non-conventional T-cells in the intra-epithelial compartment that express CD8αα and innate lymphoid cells that lack TCRs. The central feature of type 'b' IELs is the expression of CD8αα homodimers, seen in monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), which primarily arises from both CD8αα+ TCRαβ+ and CD8αα+ TCRγδ+ IELs. EATL is the other epitheliotropic T-cell lymphoma in the GI tract, a subset of which arises from the expansion and reprograming of intracytoplasmic CD3+ innate lymphoid cells, driven by IL15 and mutations of the JAK-STAT pathway.
| S-EPMC9139583 | biostudies-literature
Project description:Glioblastoma multiforme (GBM) is the most common and aggressive glial cell-derived primary tumor. Current standard of care for patients with GBM includes maximal tumor resection plus adjuvant radiotherapy and temozolomide chemotherapy, increasing median overall survival to a mere 15 months from diagnosis. Because these therapies are inherently nonspecific, there is an increased likelihood of off-target and incomplete effects; therefore, targeted modalities are required for enhanced safety and efficacy. Rindopepimut is emerging as a safe and potentially effective drug for the treatment of GBM. Rindopepimut consists of a 14-mer peptide that spans the length of EGF receptor variant III, a mutant variant of EGF receptor found on approximately 30% of primary GBM, conjugated to the carrier protein keyhole limpet hemocyanin. Vaccination with rindopepimut has been shown to specifically eliminate cells expressing EGF receptor variant III. Phase II clinical trials have suggested that vaccination of newly diagnosed GBM patients with rindopepimut plus adjuvant granulocyte-macrophage colony-stimulating factor results in prolonged progression-free and overall survival with minimal toxicity. This review will outline the development of rindopepimut, as well as the current status of this vaccine.
| S-EPMC4524671 | biostudies-literature
Project description:Post-transplant lymphoproliferative disorders (PTLDs) are life-threatening complications arising after solid organ or hematopoietic stem cell transplantations. Although the majority of these lymphoproliferations are of B cell origin, and are frequently associated with primary Epstein-Barr virus (EBV) infection or reactivation in the post-transplant period, rare cases of T cell and natural killer (NK) cell-originated PTLDs have also been described. A general assumption is that PTLDs result from the impairment of anti-viral and anti-tumoral immunosurveillance due to the long-term use of immunosuppressants in transplant recipients. T cell impairment is known to play a critical role in the immune-pathogenesis of post-transplant EBV-linked complications, while the role of NK cells has been less investigated, and is probably different between EBV-positive and EBV-negative PTLDs. As a part of the innate immune response, NK cells are critical for protecting hosts during the early response to virus-induced tumors. The complexity of their function is modulated by a myriad of activating and inhibitory receptors expressed on cell surfaces. This review outlines our current understanding of NK cells in the pathogenesis of PTLD, and discusses their potential implications for current PTLD therapies and novel NK cell-based therapies for the containment of these disorders.
| S-EPMC8068932 | biostudies-literature
Project description:Primary cutaneous CD30+ T-cell lymphoproliferative disorders are the second most common cutaneous lymphomas. According to the World Health Organization, CD30+ T-cell lymphoproliferative disorders include primary cutaneous anaplastic large cell lymphoma (C-ALCL) and lymphomatoid papulosis (LyP) as well as borderline lesions. C-ALCL and LyP are thought to represent two ends of a spectrum of diseases that have different clinical presentations, clinical courses, and prognoses in their classic forms but share the same histology of medium to large CD30+ atypical lymphoid cell infiltrates. Because the behavior of these entities is different clinically and prognostically, we aim to search for oncogenic genomic variants using whole-exome sequencing that drive the development of LyP and C-ALCL. Clinical information, pathology, immunohistochemistry, and T-cell rearrangements on six cases of LyP and five cases of C-ALCL were reviewed to confirm the rendered diagnosis before whole-exome sequencing of all specimens. Both LyP and C-ALCL had recurrent alterations in epigenetic modifying genes affecting histone methylation and acetylation (SETD2, KMT2A, KMT2D, and CREBBP). However, they also harbor unique differences with mutations in signal transducer and activator of transcription gene STAT3 of the Jak/signal transducer and activator of transcription pathway and EOMES, a transcription factor involved in lymphocyte development, only noted in C-ALCL specimens. Genomic characterization of LyP and C-ALCL in this series confirms the role of multiple pathways involved in the biology and development of these lymphomatous processes. The identification of similar aberrations within the epigenetic modifying genes emphasizes common potential development mechanisms of lymphomagenesis within lymphoproliferative disorders being shared between LyP and C-ALCL; however, the presence of differences may account for the differences in clinical course.
| S-EPMC8688881 | biostudies-literature