scholarly journals Management of prolymphocytic leukemia

Hematology ◽  
2015 ◽  
Vol 2015 (1) ◽  
pp. 361-367 ◽  
Author(s):  
Claire Dearden
Keyword(s):  
B Cell ◽  
Molecular Mechanisms ◽  
Cell Receptor ◽  
Underlying Disease ◽  
Current Therapy ◽  
Allogenic Stem Cell Transplantation ◽  
Prolymphocytic Leukemia ◽  
The Past ◽  
First Line Therapy ◽  
Purine Analog

Abstract B-cell (B-PLL) and T-cell (T-PLL) prolymphocytic leukemias are rare, poor-prognosis lymphoid neoplasms with similar presentation characterized by symptomatic splenomegaly and lymphocytosis. They can be distinguished from each other and from other T- and B-cell leukemias by careful evaluation of morphology, immunophenotyping, and molecular genetics. The clinical behavior is typically aggressive, although a subset of patients may have an indolent phase of variable length. First-line therapy for T-PLL is with intravenous alemtuzumab and for B-PLL is with combination purine analog-based chemo-immunotherapy. New B-cell receptor inhibitors, such as ibrutinib and idelalisib, may have a role in the management of B-PLL, especially for the patients harboring abnormalities of TP53. Allogenic stem cell transplantation should still be considered for eligible patients and may be the only current therapy capable of delivering a cure. In the past few years, many of the molecular mechanisms underlying disease pathogenesis and progression have been revealed and are likely to lead to the development of novel targeted approaches.

Management of prolymphocytic leukemia

Hematology ◽  
2015 ◽  
Vol 2015 (1) ◽  
pp. 361-367 ◽  
Author(s):  
Claire Dearden
Keyword(s):  
B Cell ◽  
Molecular Mechanisms ◽  
Cell Receptor ◽  
Underlying Disease ◽  
Current Therapy ◽  
Allogenic Stem Cell Transplantation ◽  
Prolymphocytic Leukemia ◽  
The Past ◽  
First Line Therapy ◽  
Purine Analog

B-cell (B-PLL) and T-cell (T-PLL) prolymphocytic leukemias are rare, poor-prognosis lymphoid neoplasms with similar presentation characterized by symptomatic splenomegaly and lymphocytosis. They can be distinguished from each other and from other T- and B-cell leukemias by careful evaluation of morphology, immunophenotyping, and molecular genetics. The clinical behavior is typically aggressive, although a subset of patients may have an indolent phase of variable length. First-line therapy for T-PLL is with intravenous alemtuzumab and for B-PLL is with combination purine analog-based chemo-immunotherapy. New B-cell receptor inhibitors, such as ibrutinib and idelalisib, may have a role in the management of B-PLL, especially for the patients harboring abnormalities of TP53. Allogenic stem cell transplantation should still be considered for eligible patients and may be the only current therapy capable of delivering a cure. In the past few years, many of the molecular mechanisms underlying disease pathogenesis and progression have been revealed and are likely to lead to the development of novel targeted approaches.

Geldanamycin-induced Lyn dissociation from aberrant Hsp90-stabilized cytosolic complex is an early event in apoptotic mechanisms in B-chronic lymphocytic leukemia

Blood ◽  
2008 ◽  
Vol 112 (12) ◽  
pp. 4665-4674 ◽  
Author(s):  
Livio Trentin ◽  
Martina Frasson ◽  
Arianna Donella-Deana ◽  
Federica Frezzato ◽  
Mario A. Pagano ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Molecular Mechanisms ◽  
Catalytic Domain ◽  
Cell Receptor ◽  
Hsp90 Inhibitor ◽  
Lymphocytic Leukemia ◽  
Early Event ◽  
Downstream Signaling ◽  
Transient Interactions

Abstract Lyn, a tyrosine kinase belonging to the Src family, plays a key role as a switch molecule that couples the B-cell receptor to downstream signaling. In B-CLL cells, Lyn is overexpressed, anomalously present in the cytosol, and displays a high constitutive activity, compared with normal B lymphocytes. The aim of this work was to gain insights into the molecular mechanisms underlying these aberrant properties of Lyn, which have already been demonstrated to be related to defective apoptosis in B-cell chronic lymphocytic leukemia (B-CLL) cells. Herein, Lyn is described to be in an active conformation as integral component of an aberrant cytosolic 600-kDa multiprotein complex in B-CLL cells, associated with several proteins, such as Hsp90 through its catalytic domain, and HS1 and SHP-1L through its SH3 domain. In particular, Hsp90 appears tightly bound to cytosolic Lyn (CL), thus stabilizing the aberrant complex and converting individual transient interactions into stable ones. We also demonstrate that treatment of B-CLL cells with geldanamycin, an Hsp90 inhibitor already reported to induce cell death, is capable of dissociating the CL complex in the early phases of apoptosis and thus inactivating CL itself. These data identify the CL complex as a potential target for therapy in B-CLL.

scholarly journals Ubiquitination of IgG1 cytoplasmic tail modulates B-cell signalling and activation

2020 ◽  
Vol 32 (6) ◽  
pp. 385-395
Author(s):  
Tadahiro Kodama ◽  
Mika Hasegawa ◽  
Yui Sakamoto ◽  
Kei Haniuda ◽  
Daisuke Kitamura
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Activation ◽  
Molecular Mechanisms ◽  
Plasma Cells ◽  
Cell Signalling ◽  
Cytoplasmic Tail ◽  
Cell Receptor ◽  
Germinal Centre ◽  
Antigen Stimulation

Abstract Upon antigen stimulation, IgG+ B cells rapidly proliferate and differentiate into plasma cells, which has been attributed to the characteristics of membrane-bound IgG (mIgG), but the underlying molecular mechanisms remain elusive. We have found that a part of mouse mIgG1 is ubiquitinated through the two responsible lysine residues (K378 and K386) in its cytoplasmic tail and this ubiquitination is augmented upon antigen stimulation. The ubiquitination of mIgG1 involves its immunoglobulin tail tyrosine (ITT) motif, Syk/Src-family kinases and Cbl proteins. Analysis of a ubiquitination-defective mutant of mIgG1 revealed that ubiquitination of mIgG1 facilitates its ligand-induced endocytosis and intracellular trafficking from early endosome to late endosome, and also prohibits the recycling pathway, thus attenuating the surface expression level of mIgG1. Accordingly, ligation-induced activation of B-cell receptor (BCR) signalling molecules is attenuated by the mIgG1 ubiquitination, except MAP kinase p38 whose activation is up-regulated due to the ubiquitination-mediated prohibition of mIgG1 recycling. Adaptive transfer experiments demonstrated that ubiquitination of mIgG1 facilitates expansion of germinal centre B cells. These results indicate that mIgG1-mediated signalling and cell activation is regulated by ubiquitination of mIgG1, and such regulation may play a role in expansion of germinal centre B cells.

scholarly journals Comparative RNA-Seq transcriptome analyses reveal dynamic time-dependent effects of 56Fe, 16O, and 28Si irradiation on the induction of murine hepatocellular carcinoma

2020 ◽  
Author(s):  
Anna M. Nia ◽  
Kamil Khanipov ◽  
Brooke L. Barnette ◽  
Robert L. Ullrich ◽  
George Golovko ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
B Cell ◽  
Acute Phase Response ◽  
Molecular Mechanisms ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Time Dependent ◽  
Rna Seq ◽  
B Cell Receptor Signaling ◽  
Cell Receptor Signaling

Abstract Background: One of the health risks posed to astronauts during deep space flights is exposure to high charge, high-energy (HZE) ions (Z>13), which can lead to induction of hepatocellular carcinoma (HCC). However, little is known on the molecular mechanisms of HZE irradiation induced HCC.Results: We performed comparative RNA-Seq transcriptomic analyses to assess the carcinogenic effects of 600 MeV/n 56 Fe (0.2 Gy), 1 GeV/n 16 O (0.2 Gy), and 350 MeV/n 28 Si (0.2 Gy) ions in a mouse model for irradiation-induced HCC. C3H/HeNCrl mice were subjected to total body irradiation to simulate space environment HZE-irradiation, and liver tissues were extracted at five different time points post-irradiation to investigate the time-dependent carcinogenic response at the transcriptomic level. Our data demonstrated a clear difference in the biological effects of these HZE ions, particularly immunological, such as Acute Phase Response Signaling, B Cell Receptor Signaling, IL-8 Signaling, and ROS Production in Macrophages. Also seen in this study were novel unannotated transcripts that were significantly affected by HZE. To investigate the biological functions of these novel transcripts, we used a machine learning technique known as self-organizing maps (SOMs) to characterize the transcriptome expression profiles of 60 samples (45 HZE-irradiated, 15 non-irradiated control) from liver tissues. A handful of localized modules in the maps emerged as groups of co-regulated and co-expressed transcripts. The functional context of these modules was discovered using overrepresentation analysis. We found that these spots typically contained enriched populations of transcripts related to specific immunological molecular processes (e.g., Acute Phase Response Signaling, B Cell Receptor Signaling, IL-3 Signaling), and RNA Transcription/Expression.Conclusions: A large number of transcripts were found differentially expressed post-HZE irradiation. These results provide valuable information for uncovering the differences in molecular mechanisms underlying HZE specific induced HCC carcinogenesis. Additionally, a handful of novel differentially expressed unannotated transcripts were discovered for each HZE ion. Taken together, these findings may provide a better understanding of biological mechanisms underlying risks for HCC after HZE irradiation, and may also have important implications for discovery of potential countermeasures against and identification of biomarkers for HZE-induced HCC.

scholarly journals FAIM: An Antagonist of Fas-Killing and Beyond

Cells ◽  
2019 ◽  
Vol 8 (6) ◽  
pp. 541 ◽  
Author(s):  
Jianxin Huo ◽  
Shengli Xu ◽  
Kong-Peng Lam
Keyword(s):  
Molecular Mechanisms ◽  
Cell Receptor ◽  
Primary Role ◽  
The Past ◽  
Pathological Conditions ◽  
Apoptotic Protein ◽  
Evolutionarily Conserved ◽  
Inhibitory Molecule ◽  
Alternatively Spliced ◽  
Fas Apoptosis Inhibitory Molecule

Fas Apoptosis Inhibitory Molecule (FAIM) is an anti-apoptotic protein that is up-regulated in B cell receptor (BCR)-activated B cells and confers upon them resistance to Fas-mediated cell death. Faim has two alternatively spliced isoforms, with the short isoform ubiquitously expressed in various tissues and the long isoform mainly found in the nervous tissues. FAIM is evolutionarily conserved but does not share any significant primary sequence homology with any known protein. The function of FAIM has been extensively studied in the past 20 years, with its primary role being ascribed to be anti-apoptotic. In addition, several other functions of FAIM were also discovered in different physiological and pathological conditions, such as cell growth, metabolism, Alzheimer’s disease and tumorigenesis. However, the detailed molecular mechanisms underlying FAIM’s role in these conditions remain unknown. In this review, we summarize comprehensively the functions of FAIM in these different contexts and discuss its potential as a diagnostic, prognostic or therapeutic target.

scholarly journals Molecular mechanisms that control expression of the B lymphocyte antigen receptor complex.

1995 ◽  
Vol 181 (1) ◽  
pp. 161-168 ◽  
Author(s):  
S A Grupp ◽  
R N Mitchell ◽  
K L Schreiber ◽  
D J McKean ◽  
A K Abbas
Keyword(s):  
B Cell ◽  
Cell Line ◽  
Heavy Chain ◽  
Molecular Mechanisms ◽  
B Lymphocyte ◽  
Cell Receptor ◽  
Surface Expression ◽  
Wild Type ◽  
Membrane Immunoglobulin ◽  
Negative Cell Line

The B cell receptor for antigen (BCR) is a complex of membrane immunoglobulin (mIg) and at least two other proteins, Ig alpha (mb-1) and Ig beta (B29). This complex promotes surface expression of the BCR and acts to transduce an activation signal. We have used a system of mu heavy chain constructs transfected into murine B cell lines to probe structure-function relationships in the BCR complex. One mutant mu chain, in which two polar transmembrane residues (Tyr587, Ser588) are replaced with valine, fails to associate with Ig alpha and Ig beta and is incapable of transducing signals as a result of mIg cross-linking. This mutant is expressed on the surface at high levels when transfected into a plasmacytoma line that lacks Ig alpha, whereas wild-type mu is retained in this cell line in the endoplasmic reticulum. Pulse-chase and immunoprecipitation analyses indicate that the mutant is more rapidly released from calnexin than the wild-type mu. Further, transfection of Ig alpha into this Ig alpha-negative cell line allows release of the mu chain from calnexin and surface expression of the BCR. These results identify the transmembrane residues of mu heavy chain that control binding to calnexin and Ig alpha, and suggest that calnexin-dependent intracellular retention is an important control mechanism for expression of the BCR complex.

scholarly journals miR-150 downregulation contributes to the high-grade transformation of follicular lymphoma by upregulating FOXP1 levels

Blood ◽  
2018 ◽  
Vol 132 (22) ◽  
pp. 2389-2400 ◽  
Author(s):  
Katerina Musilova ◽  
Jan Devan ◽  
Katerina Cerna ◽  
Vaclav Seda ◽  
Gabriela Pavlasova ◽  
...  
Keyword(s):  
B Cells ◽  
Follicular Lymphoma ◽  
B Cell ◽  
Molecular Mechanisms ◽  
B Cell Lymphoma ◽  
Cell Receptor ◽  
Upstream Region ◽  
High Grade ◽  
Histological Transformation ◽  
High Grade Transformation

Follicular lymphoma (FL) is a common indolent B-cell malignancy with a variable clinical course. An unfavorable event in its course is histological transformation to a high-grade lymphoma, typically diffuse large B-cell lymphoma. Recent studies show that genetic aberrations of MYC or its overexpression are associated with FL transformation (tFL). However, the precise molecular mechanisms underlying tFL are unclear. Here we performed the first profiling of expression of microRNAs (miRNAs) in paired samples of FL and tFL and identified 5 miRNAs as being differentially expressed. We focused on one of these miRNAs, namely miR-150, which was uniformly downmodulated in all examined tFLs (∼3.5-fold), and observed that high levels of MYC are responsible for repressing miR-150 in tFL by binding in its upstream region. This MYC-mediated repression of miR-150 in B cells is not dependent on LIN28A/B proteins, which influence the maturation of miR-150 precursor (pri-miR-150) in myeloid cells. We also demonstrated that low miR-150 levels in tFL lead to upregulation of its target, namely FOXP1 protein, which is a known positive regulator of cell survival, as well as B-cell receptor and NF-κB signaling in malignant B cells. We revealed that low levels of miR-150 and high levels of its target, FOXP1, are associated with shorter overall survival in FL and suggest that miR-150 could serve as a good biomarker measurable in formalin-fixed paraffin-embedded tissue. Overall, our study demonstrates the role of the MYC/miR-150/FOXP1 axis in malignant B cells as a determinant of FL aggressiveness and its high-grade transformation.

scholarly journals Amyloidosis in Alzheimer’s Disease: The Toxicity of Amyloid Beta (Aβ), Mechanisms of Its Accumulation and Implications of Medicinal Plants for Therapy

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Anchalee Prasansuklab ◽  
Tewin Tencomnao
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Beta ◽  
Molecular Mechanisms ◽  
Neurodegenerative Disorder ◽  
Herbal Medicines ◽  
Underlying Disease ◽  
Current Therapy ◽  
The Central Nervous System ◽  
Number Of Individuals

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that leads to memory deficits and death. While the number of individuals with AD is rising each year due to the longer life expectancy worldwide, current therapy can only somewhat relieve the symptoms of AD. There is no proven medication to cure or prevent the disease, possibly due to a lack of knowledge regarding the molecular mechanisms underlying disease pathogenesis. Most previous studies have accepted the “amyloid hypothesis,” in which the neuropathogenesis of AD is believed to be triggered by the accumulation of the toxic amyloid beta (Aβ) protein in the central nervous system (CNS). Lately, knowledge that may be critical to unraveling the hidden pathogenic pathway of AD has been revealed. This review concentrates on the toxicity of Aβand the mechanism of accumulation of this toxic protein in the brain of individuals with AD and also summarizes recent advances in the study of these accumulation mechanisms together with the role of herbal medicines that could facilitate the development of more effective therapeutic and preventive strategies.

B Cell receptor directs the activation of NFAT and NF-κB via distinct molecular mechanisms

2003 ◽  
Vol 291 (1) ◽  
pp. 11-24 ◽  
Author(s):  
Pierre Antony ◽  
James B Petro ◽  
Gianluca Carlesso ◽  
Nicholas P Shinners ◽  
John Lowe ◽  
...  
Keyword(s):  
B Cell ◽  
Molecular Mechanisms ◽  
Cell Receptor ◽  
B Cell Receptor

scholarly journals Reining in BTK: Interdomain Interactions and Their Importance in the Regulatory Control of BTK

2021 ◽  
Vol 9 ◽  
Author(s):  
Lauren E. Kueffer ◽  
Raji E. Joseph ◽  
Amy H. Andreotti
Keyword(s):  
Tyrosine Kinase ◽  
B Cell ◽  
Active Site ◽  
Molecular Mechanisms ◽  
Catalytic Domain ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Therapeutic Interventions ◽  
Regulatory Control ◽  
B Cell Malignancies

Since Dr. Ogden Bruton’s 1952 paper describing the first human primary immunodeficiency disease, the peripheral membrane binding signaling protein, aptly named Bruton’s tyrosine kinase (BTK), has been the target of intense study. Dr. Bruton’s description of agammaglobulinemia set the stage for ultimately understanding key signaling steps emanating from the B cell receptor. BTK is a multidomain tyrosine kinase and in the decades since Dr. Bruton’s discovery it has become clear that genetic defects in the regulatory domains or the catalytic domain can lead to immunodeficiency. This finding underscores the intricate regulatory mechanisms within the BTK protein that maintain appropriate levels of signaling both in the resting B cell and during an immune challenge. In recent decades, BTK has become a target for clinical intervention in treating B cell malignancies. The survival reliance of B cell malignancies on B cell receptor signaling has allowed small molecules that target BTK to become essential tools in treating patients with hematological malignancies. The first-in-class Ibrutinib and more selective second-generation inhibitors all target the active site of the multidomain BTK protein. Therapeutic interventions targeting BTK have been successful but are plagued by resistance mutations that render drug treatment ineffective for some patients. This review will examine the molecular mechanisms that drive drug resistance, the long-range conformational effects of active site inhibitors on the BTK regulatory apparatus, and emerging opportunities to allosterically target the BTK kinase to improve therapeutic interventions using combination therapies.

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