scholarly journals Bcl-xL as a Modulator of Senescence and Aging

2021 ◽  
Vol 22 (4) ◽  
pp. 1527
Author(s):  
Cristina Mas-Bargues ◽  
Consuelo Borrás ◽  
Jose Viña

Many features of aging result from the incapacity of cells to adapt to stress conditions. When cells are overwhelmed by stress, they can undergo senescence to avoid unrestricted growth of damaged cells. Recent findings have proven that cellular senescence is more than that. A specific grade of senescence promotes embryo development, tissue remodeling and wound healing. However, constant stresses and a weakening immune system can lead to senescence chronicity with aging. The accumulation of senescent cells is directly related to tissue dysfunction and age-related pathologies. Centenarians, the most aged individuals, should accumulate senescent cells and suffer from their deleterious effects, however, they enjoy a compression of morbidity. We have shown that they overexpress B-cell lymphoma-extra large (Bcl-xL). Bcl-xL could avoid an excessive burden of senescent cells through the regulation of intrinsic apoptosis, mitochondrial bioenergetics and oxidative stress. On the other hand, Bcl-xL maintains a fully functional immune system that ensures an efficient clearance of senescent cells. Moreover, there is a paradox, as inhibitors of Bcl-xL have been employed as senolytic agents, which have been shown to protect from aging in animal models. In this review, we aim to discuss how Bcl-xL could modulate senescence-associated harmful effects in centenarians, protecting them from the burden of accumulation of senescent cells.

Hematology ◽  
2007 ◽  
Vol 2007 (1) ◽  
pp. 297-303 ◽  
Author(s):  
John T. Sandlund

Abstract The SEER (Surveillance, Epidemiology, and End Results) data for the years 1975–1998 show that children with non-Hodgkin lymphoma (NHL) have a better treatment outcome than do adults. Many factors may contribute to this age-related difference. Some factors are related to the patient (e.g., drug distribution and clearance, performance status, compliance, sex) whereas others pertain to tumor histology and biology. The spectrum of NHL subtypes is well known to differ in children and adults. From ages 5 through 14 years, Burkitt lymphoma is the predominant histologic subtype, whereas diffuse large B-cell lymphoma is most common in the 15- to 29-year age range. Because different treatment strategies are often used in children and adults with NHL, the choice of therapy for adolescents and young adults (ages 15 through 29 years) is challenging and somewhat controversial. It is reasonable to consider pediatric strategies for some adolescents and very young adults with NHL, and pediatric strategies are currently used to treat adults with certain subtypes of NHL (Burkitt lymphoma, lymphoblastic lymphoma). However, the use of pediatric strategies in adults does not guarantee a comparable outcome, as illustrated by trials for adult lymphoblastic lymphoma. There is clearly a need for further biologic study of NHL in children, adolescents, and young adults. Age-related differences in tumor biology have been demonstrated in anaplastic large-cell lymphoma (ALCL) and diffuse large B-cell lymphoma (DLBCL). Additional biologic data will not only improve prognosis and treatment stratification but, more important, will lead to the identification of specific molecular targets for therapy.


2016 ◽  
Vol 28 (7) ◽  
pp. 864 ◽  
Author(s):  
Seng H. Liew ◽  
Kavitha Vaithiyanathan ◽  
Karla J. Hutt

Precisely how the length of the female fertile lifespan is regulated is poorly understood and it is likely to involve complex factors, one of which is follicle number. Indeed, the duration of female fertility appears to be intimately linked to the number of available oocytes, which are stored in the ovary as primordial follicles. There is mounting evidence implicating the intrinsic apoptosis pathway, which is controlled by members of the B-cell lymphoma-2 (BCL-2) family, as a key regulator of the number of primordial follicles established in the ovary at birth and maintained throughout reproductive life. Consequently, the pro- and anti-apoptotic BCL-2 family proteins are emerging as key determinants of the length of the female fertile lifespan. This review discusses the relationship between the intrinsic apoptosis pathway, follicle number and length of the female fertile lifespan.


Cancer ◽  
2015 ◽  
Vol 121 (16) ◽  
pp. 2858-2859 ◽  
Author(s):  
Jessica N. Williams ◽  
Ashish Rai ◽  
Christopher R. Flowers

Blood ◽  
1983 ◽  
Vol 61 (6) ◽  
pp. 1265-1268 ◽  
Author(s):  
RS Chaganti ◽  
SC Jhanwar ◽  
B Koziner ◽  
Z Arlin ◽  
R Mertelsmann ◽  
...  

Abstract A Burkitt's-like B-cell lymphoma (BLL) has recently been shown to be associated with the acquired immunodeficiency syndrome (AIDS), which affects homosexual men. We report cytogenetic studies of two BLL tumors in homosexual men. Both tumors had chromosome translocations characteristic of Burkitt's lymphoma (BL), one the t(8;14) and the other the t(8;22). The pathway of lymphomagenesis in this disorder is discussed in the light of recent data on chromosome change and localization of immunoglobulin genes and oncogenes.


Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2817-2817
Author(s):  
Noriaki Yoshida ◽  
Akira Sakai ◽  
Yoshiko Okikawa ◽  
Hideaki Nitta ◽  
Takashi Nishisaka ◽  
...  

Abstract Interleukin-2 receptor (IL2R) is usually expressed on activated T cells by antigen stimulation and on pre-B cells during B cell differentiation. Soluble IL-2R (sIL-2R) in serum is a truncated form of the 55-kDa chain of IL-2R, which is believed to be produced by cleavage by proteases. The concentration of sIL-2R in serum has been an index of tumor burden in adult T cell leukemia/lymphoma (ATL), in which CD4-positive T cells express IL-2R (CD25) on the cell surface. Subsequently, analysis of serum sIL-2R concentration has also been useful in predicting disease activity and response to treatment in B cell lymphoma. However, it is still unclear whether B cell lymphoma cells express IL-2R (CD25) or whether serum sIL-2R concentration is due to IL-2R on B cell lymphoma cells. Furthermore, it is unclear how sIL-2R is released from IL-2R in ATL. First, we examined whether serum sIL-2R concentration is a prognostic factor in previously untreated patients with DLBCL (n = 105, median age 67.0 (18–91 years)) or FL (n = 30, median age 60.0 (40–82 years)) diagnosed between January 2001 and December 2005, and who received six cycles of R + CHOP or R + THP-COP therapy. Patients who relapsed or had disease progression after R + CHOP or R + THP-COP received R + EDAP or R + ICE for DLBCL, and R + FND for FL. The 5-year OS rates for patients with sIL-2R levels of < 1500 U/ml and ⊠ 1500 U/ml were 76% and 62%, respectively (p < 0.05) in DLBCL, and 100% and 79.3%, respectively (p = 0.19) in FL. Next, we analyzed IL-2R (CD25) expression on lymphoma cells by flow cytometry. Nine of 25 patients with DLBCL and 4 of 11 patients with FL showed CD25 expression. Some T cells (CD3-positive cells) expressed CD25 in both lymphomas. On the other hand, 7 of 7 patients with MCL expressed CD25. There was no significant relationship between serum sIL-2R concentrations and CD25 expression on lymphoma cells or clinical stage in either DLBCL or FL. Metalloproteinase-9 (MMP-9) is reported to be an important protease for releasing sIL-2R from IL-2R. However, there was no significant relationship between MMP-9 and sIL-2R levels in sera from patients with DLBCL or FL. On the other hand, 7 of 7 patients with ATL showed high concentration of MMP-9 (> 128 ng/ml) irrespective of sIL-2R levels. We then confirmed MMP-9 expression in 3 ATL cell lines by Western blotting, and addition of MMP-9 inhibitor to culture media of these cell lines significantly decreased sIL-2R levels in supernatants. On immunohistochemical staining (IHC) using anti-MMP-9 antibody, macrophages not lymphoma cells or T cells were positive for MMP-9 in DLBCL and FL. These findings suggest that high serum sIL-2R concentrations in ATL are due to the cleavage of IL-2R by MMP-9 produced by ATL cells. On the other hand, the main source of sIL-2R may be due to release from activated T cells in DLBCL and FL. Therefore, serum sIL-2R levels may indicate activity of neoplastic cells in ATL; however, its levels may reflex the activity of microenviromental non-neoplastic cells in DLBCL and FL.


Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1568-1568 ◽  
Author(s):  
Jill C. Beck ◽  
Martin Bast ◽  
Deborah A. Perry ◽  
Lynette M. Smith ◽  
Dennis D. Weisenburger

Abstract Abstract 1568 Introduction Non-Hodgkin lymphoma (NHL) represents 60% of lymphoma diagnoses in children, and NHL subtypes change considerably from childhood to adulthood.[1] Recent studies have implicated age-associated biological differences in certain NHL subtypes.[2] AYAs with cancer fall between pediatric and adult patients clinically and potentially biologically. Although environmental stressors and the psychosocial transition of adolescence likely impacts these outcomes, age-related biological differences need to be better understood. The majority of pediatric NHLs are high-grade tumors, whereas low- and intermediate-grade tumors are more common among adults.[1] Recent studies have found that young adults with NHL have poorer survival compared to children.[2] Although the incidence of AYA lymphoma has increased over the past 20 years, survival has not significantly improved, demanding a better understanding of the epidemiology and biology of lymphoma among this patient population.[3] Methods Cases were identified using the Nebraska Lymphoma Study Group database and chart review. All patients with DLBCL from 1983–2010 were identified (n = 1328), and 36 (2.7%) cases are included in this study of AYA DLBCL (age 13–30 years). The Kaplan-Meier method was used to estimate overall survival (OS) and event-free survival (EFS) distributions, and the log-rank test was used to compare survival distributions between groups. OS is defined as the time from the beginning of therapy to death or last follow-up. EFS is defined as the time from the beginning of therapy to progression, death, or last follow-up. P-values less than 0.05 are considered to be statistically significant. SAS software V 9.2 (SAS Institute Inc., Cary, NC) was used for all data analysis. The study was approved by the Institutional Review Board. Results The median age of the 36 AYA DLBCL patients was 24.2 years (range, 14.5–29.8) with a female to male ratio of 1.8:1, and 53% were primary mediastinal B-cell lymphoma. Patient characteristics are shown in table 1. Of the 36 patients, 18 have died and 18 are alive at last follow-up. Fifteen deaths were due to lymphoma, 1 treatment related, 1 unrelated to disease, and 1 of unknown cause. The 5-year EFS is 52% (95% CI 34–67%, figure 1) and OS is 58% (95% CI 49–72%). The median follow-up of patients alive at last follow-up is 8.8 years (range, 1.8 – 29). OS was not affected by gender (p=0.32), stage (p=0.43), LDH (p=0.11), B symptoms (p=0.98), or size of the largest mass at diagnosis (0.93). Nearly all patients (97%) were treated on adult chemotherapy protocols. Discussion This study presents data on 36 AYA patients with DLBCL. The 5-year EFS was 52% and OS was 58%. Pediatric patients report a 5-year EFS of 87–96% [2, 4] compared to adults which have a 5-year EFS of 44–80%.[4] In contrast to other reports, in this study, gender, elevated LDH, and advanced stage (III-IV) did not impact EFS or OS, although the comparisons may be under-powered due to the small sample size. Although pediatric patients have better outcomes compared to adults, AYA patients have worse EFS than both pediatric and adult DLBCL patients, demanding further understanding of the biology of AYA DLBCL and improved treatment strategies. Disclosures: No relevant conflicts of interest to declare.


2020 ◽  
Vol 10 ◽  
Author(s):  
Yunxiong Wei ◽  
Yaqing Cao ◽  
Rui Sun ◽  
Lin Cheng ◽  
Xia Xiong ◽  
...  

B cell lymphoma 2 (BCL-2) family proteins play an important role in intrinsic apoptosis. Overexpression of BCL-2 proteins in acute myeloid leukemia can circumvent resistance to apoptosis and chemotherapy. Considering this effect, the exploration of anti-apoptotic BCL-2 inhibitors is considered to have tremendous potential for the discovery of novel pharmacological modulators in cancer. This review outlines the impact of BCL-2 family proteins on intrinsic apoptosis and the development of acute myeloid leukemia (AML). Furthermore, we will also review the new combination therapy with venetoclax that overcomes resistance to venetoclax and discuss biomarkers of treatment response identified in early-phase clinical trials.


Sign in / Sign up

Export Citation Format

Share Document