scholarly journals The Modes of Dysregulation of the Proto-Oncogene T-Cell Leukemia/Lymphoma 1A

Cancers ◽  
2021 ◽  
Vol 13 (21) ◽  
pp. 5455
Author(s):  
Johanna Stachelscheid ◽  
Qu Jiang ◽  
Marco Herling
Keyword(s):  
T Cell ◽  
Translational Regulation ◽  
B Lymphocyte ◽  
Lymphocyte Transformation ◽  
Prognostic Information ◽  
Comprehensive Overview ◽  
Aberrant Expression ◽  
Micro Rnas ◽  
Genomic Aberrations ◽  
Biological Concepts

Incomplete biological concepts in lymphoid neoplasms still dictate to a large extent the limited availability of efficient targeted treatments, which entertains the mostly unsatisfactory clinical outcomes. Aberrant expression of the embryonal and lymphatic TCL1 family of oncogenes, i.e., the paradigmatic TCL1A, but also TML1 or MTCP1, is causally implicated in T- and B-lymphocyte transformation. TCL1A also carries prognostic information in these particular T-cell and B-cell tumors. More recently, the TCL1A oncogene has been observed also in epithelial tumors as part of oncofetal stemness signatures. Although the concepts on the modes of TCL1A dysregulation in lymphatic neoplasms and solid tumors are still incomplete, there are recent advances in defining the mechanisms of its (de)regulation. This review presents a comprehensive overview of TCL1A expression in tumors and the current understanding of its (dys)regulation via genomic aberrations, epigenetic modifications, or deregulation of TCL1A-targeting micro RNAs. We also summarize triggers that act through such transcriptional and translational regulation, i.e., altered signals by the tumor microenvironment. A refined mechanistic understanding of these modes of dysregulations together with improved concepts of TCL1A-associated malignant transformation can benefit future approaches to specifically interfere in TCL1A-initiated or -driven tumorigenesis.

scholarly journals Alterations in regulatory T cells and immune checkpoint molecules in pancreatic cancer patients receiving FOLFIRINOX or gemcitabine plus nab-paclitaxel

2021 ◽  
Author(s):  
L. Sams ◽  
S. Kruger ◽  
V. Heinemann ◽  
D. Bararia ◽  
S. Haebe ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Cd8 T Cells ◽  
Mononuclear Cells ◽  
Progression Free Survival ◽  
Ductal Adenocarcinoma ◽  
Immune Checkpoints ◽  
Prognostic Information ◽  
Peripheral Blood Mononuclear

Abstract Purpose This pilot study aimed on generating insight on alterations in circulating immune cells during the use of FOLFIRINOX and gemcitabine/nab-paclitaxel in pancreatic ductal adenocarcinoma (PDAC). Patients and methods Peripheral blood mononuclear cells were isolated before and 30 days after initiation of chemotherapy from 20 patients with advanced PDAC. Regulatory T cells (FoxP3+) and immune checkpoints (PD-1 and TIM-3) were analyzed by flow cytometry and immunological changes were correlated with clinical outcome. Results Heterogeneous changes during chemotherapy were observed in circulating T-cell subpopulations with a pronounced effect on PD-1+ CD4+/CD8+ T cells. An increase in FoxP3+ or PD-1+ T cells had no significant effect on survival. An increase in TIM3+/CD8+ (but not TIM3+/CD4+) T cells was associated with a significant inferior outcome: median progression-free survival in the subgroup with an increase of TIM-3+/CD8+ T cells was 6.0 compared to 14.0 months in patients with a decrease/no change (p = 0.026); corresponding median overall survival was 13.0 and 20.0 months (p = 0.011), respectively. Conclusions Chemotherapy with FOLFIRNOX or gemcitabine/nab-paclitaxel induces variable changes in circulating T-cell populations that may provide prognostic information in PDAC.

scholarly journals Dysregulation of c-Myb Pathway by Aberrant Expression of Proto-oncogene MYB Provides the Basis for Malignancy in Adult T-cell Leukemia/lymphoma Cells

2016 ◽  
Vol 22 (23) ◽  
pp. 5915-5928 ◽  
Author(s):  
Kazumi Nakano ◽  
Kaoru Uchimaru ◽  
Atae Utsunomiya ◽  
Kazunari Yamaguchi ◽  
Toshiki Watanabe
Keyword(s):  
T Cell ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Lymphoma Cells ◽  
Aberrant Expression ◽  
Adult T Cell Leukemia

scholarly journals Immunoregulation of B lymphocyte colony formation by T cell subsets in patients with chronic lymphocytic leukemia

Blood ◽  
1986 ◽  
Vol 67 (2) ◽  
pp. 294-298
Author(s):  
LA Fernandez ◽  
JM MacSween ◽  
GR Langley
Keyword(s):  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Colony Formation ◽  
B Lymphocyte ◽  
Normal Subjects ◽  
Colony Growth ◽  
Lymphocytic Leukemia ◽  
T Cell Subsets ◽  
Cell Colony

Normal B lymphocytes are activated, proliferate, and then differentiate into plasma cells and secrete immunoglobulin (Ig). We have reported that chronic lymphocytic leukemia (CLL) T4 cells help and CLL T8 cells lack suppressor effects on Ig synthesis by normal B cells (Blood 62:767, 1983). We have now explored the earlier phase, proliferation, using B cell colony formation; in semisolid media. B lymphocyte colonies from normal individuals and from patients with CLL were grown in 0.3% agarose overlayed with T cells or T cell subsets and the B cell mitogen staphylococcal protein A. Enriched T cells, OKT4 or OKT8, were obtained either by sheep erythrocyte rosettes or depletion of OKT8 or OKT4 cells by monoclonal antibody or complement, respectively. Twenty thousand B cells from normal subjects yielded 65 +/- 9, 64 +/- 7, and 19 +/- 6 colonies with autologous unfractionated T-, OKT4-, or OKT8- positive cells, respectively. This compared to 29 +/- 11, 81 +/- 11, and 15 +/- 4 colonies from patients with CLL with added autologous unfractionated T-, OKT4-, or OKT8-positive cells. To determine whether the fewer number of colonies in both normal subjects and patients with CLL with OKT8-positive cells was due to suppression or lack of help, the number of OKT4-positive cells was held constant, and OKT8-positive cells were added in increasing numbers. No suppression of colony formation could be demonstrated. Furthermore, the addition of increasing numbers of concanavalin A (Con A)-activated OKT8-positive cells did not suppress colony formation. These results suggest that the CLL T cell subsets behave in a functionally similar manner to normal T cell subsets, namely, (1) that normal and CLL B cell colony growth is helped by OKT4 cells; and (2) in contrast to immunoglobulin secretion by B cells, neither normal nor CLL OKT8 cells, unstimulated or activated by Con A, suppress B cell colony growth.

scholarly journals Attenuation of Apoptosis Underlies B Lymphocyte Stimulator Enhancement of Humoral Immune Response

2000 ◽  
Vol 192 (7) ◽  
pp. 953-964 ◽  
Author(s):  
Richard K.G. Do ◽  
Eunice Hatada ◽  
Hayyoung Lee ◽  
Michelle R. Tourigny ◽  
David Hilbert ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cell Survival ◽  
B Lymphocyte ◽  
Humoral Immune ◽  
B Cell Survival ◽  
B Lymphocyte Stimulator

B lymphocyte stimulator (BLyS) is a newly identified monocyte-specific TNF family cytokine. It has been implicated in the development of autoimmunity, and functions as a potent costimulator with antiimmunoglobulin M in B cell proliferation in vitro. Here we demonstrate that BLyS prominently enhances the humoral responses to both T cell–independent and T cell–dependent antigens, primarily by attenuation of apoptosis as evidenced by the prolonged survival of antigen-activated B cells in vivo and in vitro. BLyS acts on primary splenic B cells autonomously, and directly cooperates with CD40 ligand (CD40L) in B cell activation in vitro by protecting replicating B cells from apoptosis. Moreover, although BLyS alone cannot activate the cell cycle, it is sufficient to prolong the survival of naive resting B cells in vitro. Attenuation of apoptosis by BLyS correlates with changes in the ratios between Bcl-2 family proteins in favor of cell survival, predominantly by reducing the proapoptotic Bak and increasing its prosurvival partners, Bcl-2 and Bcl-xL. In either resting or CD40L-activated B cells, the NF-κB transcription factors RelB and p50 are specifically activated, suggesting that they may mediate BLyS signals for B cell survival. Together, these results provide direct evidence for BLyS enhancement of both T cell–independent and T cell–dependent humoral immune responses, and imply a role for BLyS in the conservation of the B cell repertoire. The ability of BLyS to increase B cell survival indiscriminately, at either a resting or activated state, and to cooperate with CD40L, further suggests that attenuation of apoptosis underlies BLyS enhancement of polyclonal autoimmunity as well as the physiologic humoral immune response.

scholarly journals Transcription of HLA class II genes in the absence of B-cell-specific octamer-binding factor.

1988 ◽  
Vol 8 (9) ◽  
pp. 3734-3739 ◽  
Author(s):  
E Stimac ◽  
S Lyons ◽  
D Pious
Keyword(s):  
T Cell ◽  
B Cell ◽  
Cell Lines ◽  
B Lymphocyte ◽  
Class Ii ◽  
Cell Mutant ◽  
Barr Virus ◽  
Binding Factor ◽  
Epstein Barr ◽  
T Cell Lines

HLA-DR and other human class II histocompatibility genes are expressed by Epstein-Barr virus-transformed B-lymphocyte cell lines but not by most T-cell leukemia lines. We determined by transcriptional run-on experiments that regulation of class II expression in these cells is at the level of gene transcription; nuclei isolated from B-cell lines actively transcribe class II mRNA, whereas nuclei from non-class II-expressing T-cell lines and from the class II transactive factor-deficient B-cell mutant 6.1.6 do not. In searching for DNA-binding proteins which might regulate transcription, we found both a ubiquitous (B1) and a B-cell-specific (B2) factor which bind to the octamer sequence ATTTGCAT 52 base pairs 5' of the cap site in the DR alpha gene. We examined the relationship of these factors to DR alpha transcription. HUT-78, a T-cell line which expresses class II mRNA constitutively, contains only the ubiquitous B1 octamer-binding factor also found in non-class II-expressing T-cell leukemias. Human fibroblast, HeLa, and melanoma cell lines similarly contain only the ubiquitous factor, even when these cells are induced to express class II mRNA by treatment with gamma interferon. Both B1 and B2 binding factors are present in the B-cell mutant 6.1.6, which nevertheless fails to transcribe class II mRNA. Although we have not ruled out the requirement of B-cell-specific octamer-binding factor B2 for class II expression in B cells, it is clear that in other cells substantial DR alpha transcription occurs in the absence of this factor.

scholarly journals Replication history of B lymphocytes reveals homeostatic proliferation and extensive antigen-induced B cell expansion

2007 ◽  
Vol 204 (3) ◽  
pp. 645-655 ◽  
Author(s):  
Menno C. van Zelm ◽  
Tomasz Szczepański ◽  
Mirjam van der Burg ◽  
Jacques J.M. van Dongen
Keyword(s):  
Cell Proliferation ◽  
T Cell ◽  
B Cell ◽  
B Lymphocytes ◽  
Cell Expansion ◽  
B Lymphocyte ◽  
Somatic Hypermutation ◽  
Homeostatic Proliferation ◽  
History Of ◽  
Lymphocyte Homeostasis

The contribution of proliferation to B lymphocyte homeostasis and antigen responses is largely unknown. We quantified the replication history of mouse and human B lymphocyte subsets by calculating the ratio between genomic coding joints and signal joints on kappa-deleting recombination excision circles (KREC) of the IGK-deleting rearrangement. This approach was validated with in vitro proliferation studies. We demonstrate that naive mature B lymphocytes, but not transitional B lymphocytes, undergo in vivo homeostatic proliferation in the absence of somatic mutations in the periphery. T cell–dependent B cell proliferation was substantially higher and showed higher frequencies of somatic hypermutation than T cell–independent responses, fitting with the robustness and high affinity of T cell–dependent antibody responses. More extensive proliferation and somatic hypermutation in antigen-experienced B lymphocytes from human adults compared to children indicated consecutive responses upon additional antigen exposures. Our combined observations unravel the contribution of proliferation to both B lymphocyte homeostasis and antigen-induced B cell expansion. We propose an important role for both processes in humoral immunity. These new insights will support the understanding of peripheral B cell regeneration after hematopoietic stem cell transplantation or B cell–directed antibody therapy, and the identification of defects in homeostatic or antigen-induced B cell proliferation in patients with common variable immunodeficiency or another antibody deficiency.

Are T-Cell Malignancies More Frequent in Younger Children?

PEDIATRICS ◽  
1976 ◽  
Vol 57 (1) ◽  
pp. 162-162
Author(s):  
Luis Borella ◽  
Luisa Sen
Keyword(s):  
T Cell ◽  
Lymphoid Cell ◽  
B Lymphocyte ◽  
Cell Types ◽  
Lymphocyte Subpopulations ◽  
Cell Leukemia ◽  
Technical Problems ◽  
Cell Subpopulations ◽  
T Cell Malignancies ◽  
Complex Subject

Seeger and Stiehm should be congratulated on their recent careful review of a complex subject, T and B lymphocyte subpopulations.1 They correctly point out the technical problems in the identification of these cell types as well as their significance in the evaluation of certain immunological disorders. In their discussion of T-cell leukemia, however, the authors make the point that T-cell malignancies may be more frequent in younger children, on the basis of a review of lymphoid cell subpopulations by Kersey et al.2

Transcription of HLA class II genes in the absence of B-cell-specific octamer-binding factor

1988 ◽  
Vol 8 (9) ◽  
pp. 3734-3739
Author(s):  
E Stimac ◽  
S Lyons ◽  
D Pious
Keyword(s):  
T Cell ◽  
B Cell ◽  
Cell Lines ◽  
B Lymphocyte ◽  
Class Ii ◽  
Cell Mutant ◽  
Barr Virus ◽  
Binding Factor ◽  
Epstein Barr ◽  
T Cell Lines

HLA-DR and other human class II histocompatibility genes are expressed by Epstein-Barr virus-transformed B-lymphocyte cell lines but not by most T-cell leukemia lines. We determined by transcriptional run-on experiments that regulation of class II expression in these cells is at the level of gene transcription; nuclei isolated from B-cell lines actively transcribe class II mRNA, whereas nuclei from non-class II-expressing T-cell lines and from the class II transactive factor-deficient B-cell mutant 6.1.6 do not. In searching for DNA-binding proteins which might regulate transcription, we found both a ubiquitous (B1) and a B-cell-specific (B2) factor which bind to the octamer sequence ATTTGCAT 52 base pairs 5' of the cap site in the DR alpha gene. We examined the relationship of these factors to DR alpha transcription. HUT-78, a T-cell line which expresses class II mRNA constitutively, contains only the ubiquitous B1 octamer-binding factor also found in non-class II-expressing T-cell leukemias. Human fibroblast, HeLa, and melanoma cell lines similarly contain only the ubiquitous factor, even when these cells are induced to express class II mRNA by treatment with gamma interferon. Both B1 and B2 binding factors are present in the B-cell mutant 6.1.6, which nevertheless fails to transcribe class II mRNA. Although we have not ruled out the requirement of B-cell-specific octamer-binding factor B2 for class II expression in B cells, it is clear that in other cells substantial DR alpha transcription occurs in the absence of this factor.

Management of chimeric antigen receptor T-cell induced cytokine release syndrome: Current and emerging approaches

2021 ◽  
pp. 107815522110392
Author(s):  
Yunjung H Shin ◽  
Xiaofan Tian ◽  
Jiyeon J Park ◽  
Gee Y (Geeny) Kim ◽  
Emily Aboujaoude ◽  
...  
Keyword(s):  
T Cell ◽  
Chimeric Antigen Receptor ◽  
Clinical Investigation ◽  
Antigen Receptor ◽  
Common Adverse Event ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Comprehensive Overview ◽  
T Cell Therapy ◽  
First Line Therapy

The most common adverse event associated with chimeric antigen receptor T-cell therapy is cytokine release syndrome, which is characterized by fever, hypoxia, and hypotension in varying degrees of severity. In severe cases, cytokine release syndrome can result in life-threatening symptoms such as multi-organ failure. The widely accepted first-line therapy for cytokine release syndrome management is tocilizumab with or without corticosteroids, but there is very limited guidance on the proper management of patients unresponsive to this regimen. There are emerging strategies that target cytokine release syndrome through novel mechanisms, showing promise in treating or preventing severe cytokine release syndrome. Although further clinical investigation is necessary to assess the applicability of the emerging approaches, these exploratory therapies may shape the future landscape of chimeric antigen receptor T-cell induced cytokine release syndrome management. This review article provides a comprehensive overview of the current and emerging therapies for the management of chimeric antigen receptor T-cell induced cytokine release syndrome, especially cases that are refractory to tocilizumab and steroids.

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