Chidamide represses MYC expression and might improve survival for patients with double expressor lymphoma
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ABSTRACT:
SUBMITTER: Liu P
PROVIDER: S-EPMC11236771 | biostudies-literature | 2024 Jan
REPOSITORIES: biostudies-literature
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Project description:Double-expressor lymphoma (DEL), defined by MYC and BCL-2 overexpression without corresponding chromosome translocations, is often associated with poor outcomes for standard treatment (R-CHOP). Recently, inhibitors of histone deacetylases have shown great effect in T cell lymphomas. However, its effects on B cell lymphomas are mild. Here, our clinical retrospective analysis showed that HDAC inhibitor chidamide combined with R-CHOP (CR-CHOP) can dramatically increase the complete remission rate of patients with DEL. And the sensitivity of B cell lymphoma cell lines to chidamide is negatively correlated to Myc level. From Western blots and transcriptomics analysis, we found that chidamide treatment could reduce Myc protein level and downregulate the transcription levels of corresponding Myc downstream targets. Thus our results indicate that HDAC inhibitor chidamde holds great potential for treating DEL, which likely functions through inhibiting the Myc pathway.
2022-04-24 | GSE173285 | GEO
Project description:Chidamide inhibits double expressor lymphoma through repressing Myc expression and activity
| PRJNA725123 | ENA
Project description:Diffuse large B-cell lymphoma (DLBCL) is the most common and heterogeneous lymphoid malignancy. The subtype with MYC and BCL-2 double-expressor lymphoma (DEL) was defined by its aggressive nature and poor survival outcome. Therefore, the development of effective therapies for the DEL subtype is imperative. Fatty acid synthase (FASN) activity is associated with altered lipid metabolism and aberrant protein translation in DLBCL. However, the inter-regulation of these key processes is not fully determined in DEL. In the present study, the clinical and biological impact of FASN was investigated in the DEL subtype. Initially, FASN expression levels were analyzed from a patient cohort and the data indicated that the highest FASN expression was noted in DEL tissues compared with that noted in the DLBCL and reactive lymphoid hyperplasia tissues. Patients with DEL with combined high-FASN expression indicated poorer EFS outcomes than the rest of the patients. In vitro data indicated that FASN was overexpressed in SU-DHL-2 and U2932 cells. Silencing FASN decreased cell growth and promoted cell apoptosis by modulating the pERK/BCL-2 signaling pathway. In conclusion, the present study indicated that FASN was overexpressed in DEL and that its expression was associated with poor survival outcomes. Furthermore, the data demonstrated that FASN regulated the biological function via the pERK/BCL-2 signaling pathway. FASN serves a critical role in the progression of DEL and its expression may be associated with the development to a more aggressive phenotype of DLBCL. Therefore, it may be considered a potential therapeutic target for DLBCL.
| S-EPMC7882893 | biostudies-literature
Project description:BackgroundApproximately 20%-30% of diffuse large B-cell lymphoma (DLBCL) cases are classified as double-expressor lymphoma (DEL), characterized by the co-expression of the MYC and BCL2 proteins. However, the most effective therapeutic strategy for DEL remains unidentified.ObjectivesTo evaluate the efficacy of a novel histone deacetylase inhibitor, chidamide, in combination with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (CR-CHOP) in the treatment of DEL.DesignThis was a retrospective study.MethodsThis study included 62 DEL patients from December 2016 to December 2020. All patients were administered a first-line treatment with CR-CHOP. The short-term efficacy, survival status, and adverse reactions in this population were observed, and the prognostic factors were analyzed.ResultsThe median age was 53.9 years (range, 19-77). All patients received a median of six cycles (range, 1-8) of treatment, with 79.0% achieving complete response (CR) and an overall response rate of 88.7%. With a median follow-up of 45.5 months (range, 1-82), the median progression-free survival (PFS) and median overall survival (OS) had not yet been reached. However, the 3-year PFS rate was 71% (95% CI: 61-83), the 3-year OS rate was 87% (95% CI: 79-96), the 5-year PFS rate was 67% (95% CI: 55-80), and the 5-year OS rate was 85% (95% CI: 77-95). Age and autologous stem cell transplantation after CR or partial response were independent prognostic factors for PFS, while various clinical factors were not associated with OS outcomes. The most common grades 3-4 hematologic and nonhematologic toxicity were leukopenia (46.7%) and infection (21%), respectively.ConclusionThis long-term follow-up study indicates that CR-CHOP in untreated DLBCL with the DEL phenotype demonstrates high short-term efficacy and safety as well as promising survival outcomes.
| S-EPMC11528666 | biostudies-literature
Project description:Lymphoma cells expressing CD5 (CD5+) confer inferior outcome of diffuse large B-cell lymphoma (DLBCL), especially in non-MYC/BCL2 double expressor (non-DE) patients. In tumor microenvironment, CD5+ non-DE tumor revealed increased proportion of immunosuppressive M2 macrophages and enhanced pathways related to macrophage activation and migration. In accordance to M2 activation, lipid metabolism was upregulated, including fatty acid uptake and fatty acid oxidation, which supplied energy for M2 macrophage polarization and activation. Meanwhile, CD36 expression was upregulated and strongly correlated to the proportion of M2 macrophages in CD5+ non-DE DLBCL. In vitro, a DLBCL cell line (LY10) overexpressing CD5 significantly increased M2 proportion in comparison with control when cocultured with peripheral blood mononuclear cells (PBMCs). The addition of metformin significantly decreased the M2 proportion and the CD36 expression level in the coculture systems, indicating that metformin could target altered lipid metabolism and decrease M2 macrophages in DLBCL, especially in CD5+ non-DE lymphoma. In conclusion, enhanced lipid metabolism and M2 macrophage activation contributed to the immunosuppressive tumor microenvironment and could be potential therapeutic targets in CD5+ non-DE DLBCL.
| S-EPMC9583025 | biostudies-literature
Project description:BackgroundThe poor outcome of high-grade B-cell lymphoma, with rearrangements of MYC, BCL2 and/or BCL6, also known as double-hit lymphoma or triple-hit lymphoma (DHL or THL), has been well documented, while the clinical significance of extra copies of MYC, BCL2 or BCL6 are still less well known.MethodsIn total, 130 cases of diffuse large B-cell lymphoma, not otherwise specified (DLBCL-NOS) were included in our study. Fluorescence in situ hybridization and immunohistochemistry were performed in all cases to evaluate the genetic status and protein expression levels of MYC, BCL2 and BCL6.ResultsAmong the 130 cases of DLBCL, the prevalence rates of extra copies of MYC, BCL2 and BCL6 were 10.8, 20.0 and 14.6%, respectively, and the corresponding rates of gene rearrangement were 10.0, 14.6 and 16.9%, respectively. In total, 7.7% (10/130) of patients were DHL/THL; 9.2% (12/130) of patients were DLBCL with MYC and BCL2 and/or BCL6 gene abnormalities including rearrangements or extra copies, while excluded DHL/THL. The positive protein expression rates of MYC, BCL2 and BCL6 were 46.9% (61), 75.4% (98) and 70.0% (91), respectively. Among the 51 cases with MYC/BCL2 co-expression, 14 cases showed concurrence of MYC, BCL2 and/or BCL6 genetic abnormalities, and the remaining 37 cases were classified as double-expressor lymphoma (DEL). MYC and BCL2 rearrangement and BCL2 extra copies were all associated with upregulated protein expression. Cases with concurrence of MYC, BCL2 and/or BCL6 genetic abnormalities were both associated with MYC/BCL2 co-expression. Patients with concurrence of MYC, BCL2 and/or BCL6 genetic abnormalities excluded DHL/THL had shorter OS (P < 0.001) than patients with DLBCL with no genetic change, and showed no statistical different with patients with DHL/THL (P = 0.419). Extra copies of MYC was independent prognostic factors for DLBCL.ConclusionsPatients with MYC and BCL2 and/or BCL6 gene extra copies might show a trend towards poor prognosis, and the detection of extra copies of MYC, BCL2 and BCL6 might deserve more attention.
| S-EPMC6637540 | biostudies-literature
Project description:Double-hit lymphomas (DHLs) and double-expressor lymphomas (DELs) are associated with resistance to frontline and salvage immunochemotherapy, as well as autologous stem cell transplantation (SCT). We hypothesized that allogeneic SCT (alloSCT) could overcome the chemoresistance associated with DEL/DHL. We retrospectively studied the impact of DEL/DHL status in a multicenter cohort of patients who underwent alloSCT for relapsed/refractory (rel/ref) aggressive B cell non-Hodgkin lymphoma (B-NHL). Seventy-eight patients transplanted at 3 centers in whom tumor tissue was available for immunohistochemistry and fluorescence in situ hybridization were enrolled; 47% had DEL and 13% had DHL. There were no significant differences in 4-year progression-free (PFS) or overall survival (OS) between patients with DEL compared with patients without DEL (PFS 30% versus 39%, P = .24; OS 31% versus 49%, P = .17) or between patients with DHL compared with patients without DHL (PFS 40% versus 34%, P = .62; OS 50% versus 38%, P = .46). The lack of association between DEL or DHL and outcome was confirmed in multivariable models, although inadequate sample size may have limited our ability to detect significant differences. In our cohort alloSCT produced durable remissions in patients with rel/ref aggressive B-NHL irrespective of DEL and DHL status, justifying its consideration in the treatment of patients with rel/ref DEL/DHL.
| S-EPMC5826860 | biostudies-literature
Project description:BackgroundApproximately one-third of diffuse large B cell lymphoma (DLBCL) patients exhibit co-expression of MYC and BCL2 (double-expressor lymphoma, DEL) and have a dismal prognosis. Targeted inhibition of the anti-apoptotic protein BCL2 with venetoclax (ABT-199) has been approved in multiple B-cell malignancies and is currently being investigated in clinical trials for DLBCL. Whether BCL2 anti-apoptotic function represents a multifaceted vulnerability for DEL-DLBCL, affecting both lymphoma B cells and T cells within the tumor microenvironment, remains to be elucidated.MethodsHere, we present novel genetically engineered mice that preclinically recapitulate DEL-DLBCL lymphomagenesis, and evaluate their sensitivity ex vivo and in vivo to the promising combination of venetoclax with anti-CD20-based standard immunotherapy.ResultsVenetoclax treatment demonstrated specific killing of MYC+/BCL2+ lymphoma cells by licensing their intrinsically primed apoptosis, and showed previously unrecognized immunomodulatory activity by specifically enriching antigen-activated effector CD8 T cells infiltrating the tumors. Whereas DEL-DLBCL mice were refractory to venetoclax alone, inhibition of BCL2 significantly extended overall survival of mice that were simultaneously treated with a murine surrogate for anti-CD20 rituximab.ConclusionsThese results suggest that the combination of anti-CD20-based immunotherapy and BCL2 inhibition leads to cooperative immunomodulatory effects and improved preclinical responses, which may offer promising therapeutic opportunities for DEL-DLBCL patients.
| S-EPMC9980368 | biostudies-literature
Project description:Diffuse large B-cell lymphoma (DLBCL) is one of the most common causes of non-Hodgkin's lymphoma (NHL). Some of these DLBCLs can have genetic mutations as well as protein overexpression. The genes involved are MYC, BCL-2 and BCL-6. These are very aggressive and do not respond well to standard chemotherapy regiment. Lymphomas usually show classic signs and symptoms but rarely can present with little or no symptoms or even mimic other disease processes. Here we will present a case where a spinal lymphoma mimicked a hematoma and the patient developed signs and symptoms only after mechanical fall and hitting his back.
| S-EPMC7155832 | biostudies-literature
Project description:BackgroundAngioimmunoblastic T-cell lymphoma (AITL) is known for its unfavorable survival prognosis. Chidamide has shown efficacy in relapsed/refractory AITL, but its efficacy in newly diagnosed AITL is uncertain.ObjectiveThis retrospective research aimed to evaluate the effectiveness and safety of chidamide when used with doxorubicin, cyclophosphamide, prednisone, and vincristine (CHOP) in comparison to CHOP by itself for individuals newly diagnosed with AITL, and to examine the impact of transplantation.MethodThis was an analysis that compared outcomes among patients who received chidamide + CHOP on a clinical trial vs. historical controls who received CHOP alone, enrolling a total of sixty-six treatment-naive AITL patients between April 2014 and November 2022. Among them, thirty-three received chidamide in addition to CHOP (chidamide group), while thirty-three received CHOP alone (control group). The clinical characteristics were balanced between the two groups. All patients were scheduled to undergo up to six courses of treatment before transplantation.ResultsThe chidamide group had a significantly longer median overall survival (OS) compared to the control group, with a median OS that was not reached, as opposed to 20 months in the control group (p = 0.002). In the control group, the median progression-free survival (PFS) was 11 months, while in the chidamide group, it was 22 months (p = 0.080). In the high-risk group (IPI ≥ 3), the chidamide group demonstrated notably superior complete response (CR) and overall response rate (ORR) compared to the control cohort (p = 0.002, p = 0.034). The PFS and OS in the chidamide group were not reached, and there were significant differences compared to the control group (p = 0.007, p = 0.003). The median OS of the transplanted group was longer than the non-transplanted group (p = 0.004). On multivariate analysis, chidamide group reduced the hazards of death in the total cohort.ConclusionAs the study was non-random and retrospective, Chidamide combined with chemotherapy should be tested in randomized trials given its potential to improve prognosis in treatment-naive AITL patients. Furthermore, autologous hematopoietic stem cell transplantation (auto-HSCT) has demonstrated enhanced overall survival in individuals with AITL.Clinical trial registrationhttps://clinicaltrials.gov/, NCT03268889.
| S-EPMC11368836 | biostudies-literature