The defect in peripheral blood B-cell activation in patients with multiple myeloma is not due to a deficiency in the production of B-cell growth and differentiation factors

1989 ◽  
Vol 9 (1) ◽  
pp. 65-73 ◽  
Author(s):  
Th�r�se Commes ◽  
Bernard Klein ◽  
Michel Jourdan ◽  
Gis�le Clofent ◽  
Fr�d�ric Houssiau ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Growth ◽  
B Cell ◽  
Peripheral Blood ◽  
Cell Activation ◽  
B Cell Activation ◽  
Differentiation Factors ◽  
Cell Growth And Differentiation

B Cell Growth and Differentiation Factors and Mechanism of B Cell Activation

1984 ◽  
Vol 78 (1) ◽  
pp. 97-118 ◽  
Author(s):  
T. Kishimoto ◽  
K. Yoshizaki ◽  
M. Kimoto ◽  
M. Okada ◽  
T. Kuritani ◽  
...  
Keyword(s):  
Cell Growth ◽  
B Cell ◽  
Cell Activation ◽  
B Cell Activation ◽  
Differentiation Factors ◽  
Cell Growth And Differentiation

scholarly journals Telomerase Activity Is Induced in Human Peripheral B Lymphocytes by the Stimulation to Antigen Receptor

Blood ◽  
1997 ◽  
Vol 89 (4) ◽  
pp. 1299-1307 ◽  
Author(s):  
Hideya Igarashi ◽  
Nobuo Sakaguchi
Keyword(s):  
B Cells ◽  
B Cell ◽  
Peripheral Blood ◽  
Cell Activation ◽  
Interleukin 2 ◽  
Antigen Receptor ◽  
Telomerase Activity ◽  
B Cell Activation ◽  
Molecular Events

Abstract To understand the molecular events for the proliferation of B cells, we studied the induction of telomerase activity in vitro after stimulation to B-cell antigen receptor (BCR) on human peripheral B cells. Although unstimulated purified B cells of tonsils and peripheral blood from healthy volunteers do not express detectable telomerase activity, anti-IgM beads induce telomerase activity in these B cells. Soluble anti-IgM antibody (Ab) alone does not induce telomerase activity, but the second signal, given by either one of the cytokines of interleukin-2 (IL-2), IL-4, and IL-13 or by anti-CD40 monoclonal Ab (MoAb), is effective as the costimulation for the induction of the activity. Stimulation with antiIgM Ab and anti-CD40 MoAb induces telomerase activity in most mature B cells of the tonsils and peripheral blood. The stimuli to both IgM and IgD receptors similarly induce the activity. Induction of telomerase activity is accompanied with the proliferation of B cells, but is not absolutely correlated with the extent of B-cell growth. Phorbol dibutylate (PDB) plus calcium (Ca) ionophore (PDB/Ca), which replace the activation through BCR and the costimulatory molecules, also induce telomerase activity. Moreover, it is suggested that phosphoinositide (PI) 3-kinase plays a role for the induction of telomerase activity in B cells stimulated with anti-IgM Ab and anti-CD40 MoAb. These results suggest that telomerase activity is induced in the B-cell activation of the antigen specific immune response.

B Cell Growth and Differentiation Factors

1984 ◽  
Vol 78 (1) ◽  
pp. 185-210 ◽  
Author(s):  
Maureen Howard ◽  
Kenji Nakanishi ◽  
WilliamE. Paul
Keyword(s):  
Cell Growth ◽  
B Cell ◽  
Differentiation Factors ◽  
Cell Growth And Differentiation

scholarly journals An IRF4-MYC-mTORC1 integrated pathway controls cell growth and the proliferative capacity of activated B cells during B cell differentiation in vivo

2021 ◽  
Author(s):  
Dillon G Patterson ◽  
Anna K Kania ◽  
Madeline J Price ◽  
James R Rose ◽  
Christopher D Scharer ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Differentiation ◽  
B Cells ◽  
Cell Growth ◽  
B Cell ◽  
Proliferative Response ◽  
Cell Activation ◽  
B Cell Differentiation ◽  
B Cell Activation

Cell division is an essential component of B cell differentiation to antibody-secreting plasma cells, with critical reprogramming occurring during the initial stages of B cell activation. However, a complete understanding of the factors that coordinate early reprogramming events in vivo remain to be determined. In this study, we examined the initial reprogramming by IRF4 in activated B cells using an adoptive transfer system and mice with a B cell-specific deletion of IRF4. IRF4-deficient B cells responding to influenza, NP-Ficoll and LPS divided, but stalled during the proliferative response. Gene expression profiling of IRF4-deficient B cells at discrete divisions revealed IRF4 was critical for inducing MYC target genes, oxidative phosphorylation, and glycolysis. Moreover, IRF4-deficient B cells maintained an inflammatory gene expression signature. Complementary chromatin accessibility analyses established a hierarchy of IRF4 activity and identified networks of dysregulated transcription factor families in IRF4-deficient B cells, including E-box binding bHLH family members. Indeed, B cells lacking IRF4 failed to fully induce Myc after stimulation and displayed aberrant cell cycle distribution. Furthermore, IRF4-deficient B cells showed reduced mTORC1 activity and failed to initiate the B cell-activation unfolded protein response and grow in cell size. Myc overexpression in IRF4-deficient was sufficient to overcome the cell growth defect. Together, these data reveal an IRF4-MYC-mTORC1 relationship critical for controlling cell growth and the proliferative response during B cell differentiation.

scholarly journals An increase in circulating B cells and B cell activation markers in peripheral blood is associated with cigarette smoking in a male cohort in Bangladesh

2019 ◽  
Vol 384 ◽  
pp. 114783
Author(s):  
Scott W. Burchiel ◽  
Fredine T. Lauer ◽  
Pam Factor-Litvak ◽  
Xinhua Liu ◽  
Regina M. Santella ◽  
...  
Keyword(s):  
B Cells ◽  
Cigarette Smoking ◽  
B Cell ◽  
Peripheral Blood ◽  
Cell Activation ◽  
B Cell Activation ◽  
Activation Markers ◽  
Male Cohort

Targeting Bruton's Tyrosine Kinase As a Novel Approach to Inhibit Osteoclast Function in Multiple Myeloma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2882-2882
Author(s):  
Homare Eda ◽  
Loredana Santo ◽  
Diana D. Cirstea ◽  
Samantha Pozzi ◽  
Miriam Canavese ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
B Cell ◽  
Board Of Directors ◽  
Cell Activation ◽  
B Cell Activation ◽  
Advisory Committees ◽  
Pit Formation ◽  
Btk Inhibitor ◽  
Equity Ownership ◽  
Rank Signaling

Abstract Abstract 2882 Bone disease is a hallmark of multiple myeloma (MM) and targeting osteoclasts (OC) to alleviate bone destruction is a component of the standard of care for MM. The activation of Bruton's tyrosine kinase (Btk), a member of the Tec family of tyrosine kinases, regulates B-cell activation and development and plays an important role in antibody production. Interestingly, Btk activation also occurs downstream of RANK signaling in OCs and its activation stimulates essential calcium signaling which plays an important role in OC function. Given this dual role of BTK in both B cell activation and osteoclastogenesis, we studied its role in the context of multiple myeloma (MM). Accordingly, we examined the efficacy of a potent and specific inhibitor of Btk (AVL-292) in OCs derived from MM patient monocytes. AVL-292 is a highly selective, covalent Btk inhibitor that potently silences Btk enzymatic activity (IC50 < 0.5nM) and inhibits primary B cell proliferation and activation (EC50 ∼ 10nM). The compound showed high selectivity towards Btk when tested in a broad kinase panel of 62 kinases and importantly did not show significant inhibition against other kinases involved in BCR signaling (Syk, Lyn). OC derived from MM patient monocytes were assayed with or without AVL-292 for OC maturation by TRAP staining and functional activity by resorptive pit formation assay. OC function was inhibited in the presence of AVL-292 as determined by a decrease in pit formation. To delineate the mechanism of action of AVL-292 against OC function, the RANK signaling proteins were detected by western blotting and intracellular Ca2+ concentration was measured by fluorescence. AVL-292 inhibited phosphorylation of the Btk substrate, PLC γ2 in OCs. This was associated with an inhibition of intracellular Ca2+ release by AVL-292 which otherwise increased with RANKL stimulation in OCs. Although AVL-292 did not demonstrate direct cytotoxicity or inhibition of proliferation of MM cells, ongoing studies are confirming its activity in the context of co-cultures with accessory cells like OCs. These data demonstrate that the novel BTK inhibitor AVL-292 inhibits OC function through inhibition of Ca2+ mobilization through RANK signaling. These results suggest inhibition of Btk with AVL-292 has therapeutic potential for the treatment of myeloma related bone disease. Disclosures: Evans: Avila Therapeutics: Employment, Equity Ownership. Singh:Avila Therapeutics: Employment, Equity Ownership. Raje:Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Acetylon: Research Funding.

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