B cell receptor signaling in chronic lymphocytic leukemia.
TL;DR: The evolution of this field is discussed, from BCR-related prognostic markers, to mechanisms of BCR activation, and targeting of B CR-associated kinases, the emerging Achilles' heel in CLL pathogenesis.
About: This article is published in Trends in Immunology.The article was published on 2013-12-01 and is currently open access. It has received 378 citations till now. The article focuses on the topics: B-cell receptor & Chronic lymphocytic leukemia.
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TL;DR: A large number of patients diagnosed with chronic lymphocytic leukemia have a history of atypical clinical course, suggesting that the disease typically occurs in elderly patients and has a highly variable clinical course.
Abstract: Disease Overview
Chronic lymphocytic leukemia (CLL) is the commonest leukemia in western countries. The disease typically occurs in elderly patients and has a highly variable clinical course. Leukemic transformation is initiated by specific genomic alterations that impair apoptosis of clonal B cells.
Diagnosis
The diagnosis is established by blood counts, blood smears, and immunophenotyping of circulating B lymphocytes, which identify a clonal B-cell population carrying the CD5 antigen and B-cell markers.
Prognosis
Two prognostic staging systems exist, the Rai and Binet staging systems, which are established by physical examination and blood counts. Various biological and genetic markers also have prognostic value. Deletions of the short arm of chromosome 17 (del(17p)) and/or mutations of the TP53 gene predict resistance to available chemotherapies. A comprehensive prognostic score (CLL-IPI) using genetic, biological, and clinical variables has recently been developed allowing to classify CLL into very distinct risk groups.
Therapy
Patients with active or symptomatic disease or with advanced Binet or Rai stages require therapy. For physically fit patients, chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab remains the current standard therapy. For unfit patients, currently available evidence supports two options for a first-line therapy: chlorambucil combined with an anti-CD20 antibody (obinutuzumab or rituximab or ofatumumab) or a continuous therapy with ibrutinib. At relapse, the initial treatment may be repeated, if the treatment-free interval exceeds 3 years. If the disease relapses earlier, therapy should be changed using alternative agents such as bendamustine (plus rituximab), alemtuzumab, lenalidomide, ofatumumab, ibrutinib, idelalisib, or venetoclax. Patients with a del(17p) or TP53 mutation can be treated with ibrutinib, venetoclax, or a combination of idelalisib and rituximab. An allogeneic SCT may be considered in relapsing patients with TP53 mutations or del(17p) or patients that are refractory to chemoimmunotherapy and the novel inhibitors.
Future Challenges
The new agents (ibrutinib, idelalisib, venetoclax, and obinutuzumab) hold the potential to significantly improve the outcome of CLL patients. However, their optimal use (in terms of combination, sequence, and duration) remains unknown. Therefore, CLL patients should be treated in clinical trials whenever possible.
270 citations
Cites background from "B cell receptor signaling in chroni..."
...B-cell receptor signaling seems to play an important role for the survival of CLL cells.(94,95) Different aspects of the B-cell receptor have been recognized as a prognostic marker in CLL, such as HALLEK AJH | 951...
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TL;DR: Chronic lymphocytic leukemia is the commonest leukemia in western countries and typically occurs in elderly patients and has a highly variable clinical course.
Abstract: Disease overview: Chronic lymphocytic leukemia (CLL) is the commonest leukemia in western countries. The disease typically occurs in elderly patients and has a highly variable clinical course. Leukemic transformation is initiated by specific genomic alterations that impair apoptosis of clonal B-cells.
Diagnosis: The diagnosis is established by blood counts, blood smears, and immunophenotyping of circulating B-lymphocytes, which identify a clonal B-cell population carrying the CD5 antigen as well as B-cell markers.
Prognosis: Two prognostic staging systems exist, the Rai and Binet staging systems, which are established by physical examination and blood counts. Various biological and genetic markers also have prognostic value. Deletions of the short arm of chromosome 17 (del(17p)) predict resistance to available chemotherapies. Comprehensive prognostic scores are currently being developed.
Therapy: Patients with active or symptomatic disease or with advanced Binet or Rai stages require therapy. For physical fit patients, chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab remains the current standard therapy. For unfit patients, treatment with an anti-CD20 antibody (obinutuzumab or rituximab or ofatumumab) plus a milder chemotherapy (Chlorambucil) may be applied. At relapse, the initial treatment may be repeated, if the treatment-free interval exceeds two to three years. If the disease relapses earlier, therapy should be changed using alternative agents such as bendamustine (plus rituximab), alemtuzumab, lenalidomide, ofatumumab, ibrutinib, or idelalisib. Patients with a del(17p) or TP53 mutation can be treated with ibrutinib or a combination of idelalisib and rituximab. An allogeneic SCT may be considered in relapsing patients with TP53 mutations or del(17p) or patients that are refractory to repeated chemoimmunotherapies.
Future challenges: Several new agents (e.g., ibrutinib, idelalisib, obinutuzumab) hold the potential to improve the outcome of patients with CLL. However, their optimal use (in terms of combination, sequence, and duration) is unknown. Therefore, CLL patients should be treated in clinical trials whenever possible.Am. J. Hematol. 90:447–460, 2015. © 2015 Wiley Periodicals, Inc.
254 citations
Cites background from "B cell receptor signaling in chroni..."
...B-cell receptor signaling seems to play an important role for the survival of CLL cells [84,85]....
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TL;DR: B cells and B CR-related kinases also play a role in the microenvironment of solid tumours, such as squamous cell carcinoma and pancreatic cancer, and therefore targeting B cells or BCR- related kinases may have anticancer activity beyond B cell malignancies.
Abstract: B cell receptor (BCR) signalling is crucial for normal B cell development and adaptive immunity. BCR signalling also supports the survival and growth of malignant B cells in patients with B cell leukaemias or lymphomas. The mechanism of BCR pathway activation in these diseases includes continuous BCR stimulation by microbial antigens or autoantigens present in the tissue microenvironment, activating mutations within the BCR complex or downstream signalling components and ligand-independent tonic BCR signalling. The most established agents targeting BCR signalling are Bruton tyrosine kinase (BTK) inhibitors and PI3K isoform-specific inhibitors, and their introduction into the clinic is rapidly changing how B cell malignancies are treated. B cells and BCR-related kinases, such as BTK, also play a role in the microenvironment of solid tumours, such as squamous cell carcinoma and pancreatic cancer, and therefore targeting B cells or BCR-related kinases may have anticancer activity beyond B cell malignancies.
249 citations
TL;DR: This Review focuses on recent insights into the understanding of CLL biology, with emphasis on the role of genetic lesions in the initiation and clinical progression of Cll.
Abstract: Recent investigations have provided an increasingly complete picture of the genetic landscape of chronic lymphocytic leukaemia (CLL). These analyses revealed that the CLL genome displays a high degree of heterogeneity between patients and within the same patient. In addition, they highlighted molecular mechanisms and functionally relevant biological programmes that may be important for the pathogenesis and therapeutic targeting of this disease. This Review focuses on recent insights into the understanding of CLL biology, with emphasis on the role of genetic lesions in the initiation and clinical progression of CLL. We also consider the translation of these findings into the development of risk-adapted and targeted therapeutic approaches.
229 citations
TL;DR: It is demonstrated that the ibrutinib therapy favours selection and expansion of rare subclones already present before ibrUTinib treatment, and insight is provided into the heterogeneity of genetic changes associated with ibrutsinib resistance.
Abstract: Resistance to the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib has been attributed solely to mutations in BTK and related pathway molecules Using whole-exome and deep-targeted sequencing, we dissect evolution of ibrutinib resistance in serial samples from five chronic lymphocytic leukaemia patients In two patients, we detect BTK-C481S mutation or multiple PLCG2 mutations The other three patients exhibit an expansion of clones harbouring del(8p) with additional driver mutations (EP300, MLL2 and EIF2A), with one patient developing trans-differentiation into CD19-negative histiocytic sarcoma Using droplet-microfluidic technology and growth kinetic analyses, we demonstrate the presence of ibrutinib-resistant subclones and estimate subclone size before treatment initiation Haploinsufficiency of TRAIL-R, a consequence of del(8p), results in TRAIL insensitivity, which may contribute to ibrutinib resistance These findings demonstrate that the ibrutinib therapy favours selection and expansion of rare subclones already present before ibrutinib treatment, and provide insight into the heterogeneity of genetic changes associated with ibrutinib resistance
220 citations
References
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TL;DR: In this paper, the authors sequenced the Ig V(H) genes of the tumor cells of 84 patients with CLL and correlated their findings with clinical features, finding that the lack of somatic mutation and trisomy 12 was associated with a less favorable prognosis.
2,704 citations
TL;DR: In this paper, cellular immunophenotypic studies were performed on a cohort of randomly selected IgM(+) B-chronic lymphocytic leukemia (B-CLL) cases for which Ig V(H) and V(L) gene sequences were available.
2,388 citations
TL;DR: Ibrutinib was associated with a high frequency of durable remissions in patients with relapsed or refractory CLL and small lymphocytic lymphoma, including patients with high-risk genetic lesions.
Abstract: Background The treatment of relapsed chronic lymphocytic leukemia (CLL) has resulted in few durable remissions. Bruton's tyrosine kinase (BTK), an essential component of B-cell–receptor signaling, mediates interactions with the tumor microenvironment and promotes the survival and proliferation of CLL cells. Methods We conducted a phase 1b–2 multicenter study to assess the safety, efficacy, pharmacokinetics, and pharmacodynamics of ibrutinib (PCI-32765), a first-in-class, oral covalent inhibitor of BTK designed for treatment of B-cell cancers, in patients with relapsed or refractory CLL or small lymphocytic lymphoma. A total of 85 patients, the majority of whom were considered to have high-risk disease, received ibrutinib orally once daily; 51 received 420 mg, and 34 received 840 mg. Results Toxic effects were predominantly grade 1 or 2 and included transient diarrhea, fatigue, and upper respiratory tract infection; thus, patients could receive extended treatment with minimal hematologic toxic effects. The...
1,988 citations
TL;DR: From the Institute for Medical Research, North Shore–LIJ Health System (N.R.R.), and the Departments of Medicine, North shore University Hospital, Manhasset, N.Y. (K.C., K.R.) and the Dipartimento di Oncologia Clinica e Sperimentale, Universitá di Genova (M.F.).
Abstract: From the Institute for Medical Research, North Shore–LIJ Health System (N.C., K.R.R.), and the Departments of Medicine, North Shore University Hospital, Manhasset, N.Y., and New York University School of Medicine, New York (N.C.); the Departments of Medicine, Long Island Jewish Medical Center, New Hyde Park, N.Y., and Albert Einstein School of Medicine, Bronx, N.Y. (K.R.R.); and the Division of Medical Oncology C, Istituto Nazionale per la Ricerca sul Cancro, and the Dipartimento di Oncologia Clinica e Sperimentale, Universitá di Genova — both in Genoa, Italy (M.F.). Address reprint requests to Dr. Chiorazzi at the Institute for Medical Research, North Shore–LIJ Health System, 350 Community Dr., Manhasset, NY 11030, or at nchizzi@nshs.edu.
1,667 citations
TL;DR: Findings establish chronic active BCR signalling as a new pathogenetic mechanism in ABC DLBCL, suggesting several therapeutic strategies.
Abstract: A role for B-cell-receptor (BCR) signalling in lymphomagenesis has been inferred by studying immunoglobulin genes in human lymphomas and by engineering mouse models, but genetic and functional evidence for its oncogenic role in human lymphomas is needed. Here we describe a form of 'chronic active' BCR signalling that is required for cell survival in the activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL). The signalling adaptor CARD11 is required for constitutive NF-kappaB pathway activity and survival in ABC DLBCL. Roughly 10% of ABC DLBCLs have mutant CARD11 isoforms that activate NF-kappaB, but the mechanism that engages wild-type CARD11 in other ABC DLBCLs was unknown. An RNA interference genetic screen revealed that a BCR signalling component, Bruton's tyrosine kinase, is essential for the survival of ABC DLBCLs with wild-type CARD11. In addition, knockdown of proximal BCR subunits (IgM, Ig-kappa, CD79A and CD79B) killed ABC DLBCLs with wild-type CARD11 but not other lymphomas. The BCRs in these ABC DLBCLs formed prominent clusters in the plasma membrane with low diffusion, similarly to BCRs in antigen-stimulated normal B cells. Somatic mutations affecting the immunoreceptor tyrosine-based activation motif (ITAM) signalling modules of CD79B and CD79A were detected frequently in ABC DLBCL biopsy samples but rarely in other DLBCLs and never in Burkitt's lymphoma or mucosa-associated lymphoid tissue lymphoma. In 18% of ABC DLBCLs, one functionally critical residue of CD79B, the first ITAM tyrosine, was mutated. These mutations increased surface BCR expression and attenuated Lyn kinase, a feedback inhibitor of BCR signalling. These findings establish chronic active BCR signalling as a new pathogenetic mechanism in ABC DLBCL, suggesting several therapeutic strategies.
1,463 citations