Abstract Loss of function of PAX5 plays an important role in PAX5 mutation tumor, and PAX5 haploinsufficiency promoting tumorigenesis is related to immune escape. But the mechanisms of PAX5 mutations inducing tumor immune escape have not been clarified. We estimated the proportions of 22 immune cell types and the expressions of immune inhibitory-related molecules based on gene expression profiles (GEPs) from B- acute lymphoblastic leukemia(B-ALL) with PAX5 mutations by CIBERSORT, an established algorithm. We constructed the PAX5 haplodeletion A20 cell lines, built allografted A20 tumor models and evaluated the effect of PAX5 haplodeletion on immune inhibitory-related molecules in the tumor microenvironment (TME). Our results indicated the percentages of T cells in bone marrow of B-ALL with PAX5 mutations were not statistically different from that in bone marrow of B-ALL without PAX5 mutations, except for T follicular helper (Tfh) cells. But a variety of up-regulated immune inhibitory-related molecules in bone marrow of B- ALL with PAX5 mutations were identified. By different approaches, we found that several immune inhibitory-related molecules of CD8+ T cells in TME of PAX5 haplodeletion clones such as TIM3, NR4A1 and BATF, were increased significantly compared with that of PAX5 wild type control. The IFN-ɤ of CD8+ T cells in TME of PAX5 haplodeletion tumors was decreased significantly compared with that of PAX5 wild type control. Our study showed that PAX5 haploinsufficiency induced high expressions of TIM3, NR4A1 and BATF in the TME and was involved in CD8+ T cells dysfunction or exhaustion.
Background: The response rate of traditional first-line induction chemotherapy (IC) for newly diagnosed acute myeloid leukemia needs to be improved, but it is not clear whether adding venetoclax or hypomethylating agents (HMAs) to IC will improve the response rate. Objective: To determine whether venetoclax or HMAs could increase the response rate of IC in patients with newly diagnosed acute myeloid leukemia (AML). Design: A retrospective, propensity score matching analysis. Methods: Newly diagnosed AML patients at Tongji Hospital between 2021 and 2023 were included in this study. By matching cases and controls based on age, gender, baseline bone marrow blast cell proportion, type of AML, and the National Comprehensive Cancer Network (NCCN) risk stratification group, we compared the response rate (CR, CR/CRi, ORR, and MRD negative) and hematological adverse events in newly diagnosed AML treated with IC plus venetoclax or HMAs versus IC alone after one cycle of IC. Results: The addition of venetoclax could improve CR/CRi of IC (83.8% for IC plus venetoclax vs 66.1% for IC alone, p = 0.029). The addition of venetoclax to IA regimen did not improve CR/CRi of IA regimen (76.9% for IA plus venetoclax vs 76.2% for IA alone, p = 0.986). The addition of HMAs could not only improves CR/CRi of IC (85.3%% for IC plus HMAs vs 65.4% for IC alone, p = 0.002) but also improves CR/CRi of IA regimen (91.3% for IA plus HMAs vs 70.0% for IA alone, p = 0.034). The addition of HMAs could improve CR/CRi of patients with adverse mutations (FLT3, IDH1/2, K/NRAS) after IC. The addition of venetoclax and HMAs both extended the duration of agranulocytosis and thrombocytopenia. Conclusion: Adding HMAs might improve CR/CRi of IC including IA. Adding venetoclax might not improve CR/CRi of IA. A well-designed prospective randomized controlled study is now warranted.
Background:: The tumor burden before chimeric antigen receptor T (CAR-T) cell therapy was one of the critical factors affecting the prognosis of lymphoma. It was a challenge to effectively reduce the tumor burden of relapsed/refractory large B-cell lymphoma with p53 mutation. Objective:: Here, we have presented a case of relapsed/refractory large B-cell lymphoma with p53 mutation being controlled by the treatment with daratumumab and venetoclax, followed by CAR-T cell therapy. Case Presentation:: The patient was a 56-year-old female who was diagnosed with relapsed/ refractory diffuse large B cell lymphoma (DLBCL) transformed from follicular lymphoma. The patient was treated with daratumumab, venetoclax, and GEMOX (gemcitabine and oxaliplatin) under the guidance of high-throughput drug sensitivity analysis. We used a CD38 positive lymphoma cell line with p53 mutation to construct tumor models for validating the anti- lymphoma effect of the combination therapy of daratumumab and venetoclax. Results:: The patient achieved a complete metabolic response after treatment with daratumumab, venetoclax, and GEMOX. Then, she further achieved a complete molecular response after she subsequently received CAR-T cell therapy, and she has been living without a lymphoma recurrence. The results from the animal study showed that the combination of daratumumab and venetoclax could significantly enhance the antitumor effect on CD38-positive lymphoma with p53 mutation./ Conclusion:: The results from our successful case and animal experiments provide new avenues for the treatment of relapsed/refractory large B-cell lymphoma with p53 mutation. Further clinical trials are reuqired to treat CD38-positive lymphoma with the combination of daratumumab and venetoclax.
Abstract Background:PAX5 mutations are involved in the development and recurrence of leukemia. There were few studies on how PAX5 mutations influencing leukemia bone marrow microenvironment. Methods: We obtained the mRNA profiling of B-acute lymphoblastic leukemia(ALL) patients from GSE11877 and the clinical features (including molecular genetics) from the literature. We identified differentially expressed genes (DEGs) between B-ALL with PAX5 mutations and B-ALL without PAX5 mutations in leukemia microenvironment using the LIMMA package of R. We assessed immune cell types by CIBERSORT. DEGs were analyzed using the DAVID,STRING and Coexpedia. Results:The results from CIBERSORT analysis showed that M0 macrophages were significantly increased from ALL PAX5 mutations. The results from DAVID analysis indicated that these DEGs were mostly involved in phosphorylation and antigen presentation from biological process categories. These DEGs may be involved in changes in macrophages. Other analyses from PPI network and co -expression network found three common genes such as IL1B, CD34, PDGFRB, which were highly related to angiogenesis. Conclusions:These changes hinted that PAX5 mutations led to macrophage changes, and macrophage changes were related to processes of antigen presentation and angiogenesis in leukemia microenvironment.
Rationale: The coexistence of the extranidal marginal zone lymphoma (MZL) of mucosa–associated lymphoid tissue (MALT) and multiple myeloma (MM) is an exceedingly rare situation. The rare situation precludes any evidence-based guidelines for MZL or MM. Patient concerns and diagnoses: We presented a unique case of the coexistence of primary mediastinal MALT lymphoma and MM like polyneuropathy, organomegaly, endocrinopathy, M-protein, skin syndrome. Interventions and outcomes: The patient was first diagnosed with polyneuropathy, organomegaly, endocrinopathy, M-protein, skin syndrome in the department of neurology, then MM in the department of hematology, and the mediastinal MALT simultaneously coexisting with MM was found by biopsy in the department of thoracic surgery. The patient received combination therapy with rituximab and bortezomib followed by lenalidomide maintenance. To understand MZL lymphoma with plasmacytic differentiation better, we analyzed cases of MZL lymphomas with plasma cell neoplasms. Most of these cases were MZL lymphomas with light chain-restricted plasmacytic differentiation. The lymphomas relapsed with plasma cell neoplasms or transformed into plasma cell neoplasms after anti-lymphoma therapy. Lessons: The case demonstrated clinical complexity and the importance of the detailed assessment. The case and literature review demonstrated the value of detecting light chain-restricted plasmacytic differentiation for the treatment of MZL lymphoma with rituximab plus lenalidomide or bortezomib.
PAX5 haploinsufficiency promoting tumorigenesis is related to immune escape. But the mechanisms of PAX5 mutations inducing tumor immune escape have not been clarified. Our aim was to study how PAX5 haploinsufficiency influences effector CD8 + T cells in tumor microenvironment. We estimated the proportions of 22 immune cell types and the expressions of immune inhibitory-related molecules based on gene expression profiles (GEPs) from children's B- acute lymphoblastic leukemia(B-ALL) with PAX5 mutations by CIBERSORT, an established algorithm. We constructed the PAX5 haplodeletion A20 cell lines, built allografted A20 tumor models and evaluated the effect of PAX5 haplodeletion on immune inhibitory-related molecules in the tumor microenvironment (TME). Our results indicated the percentages of T cells in bone marrow of children's B-ALL with PAX5 mutations were not statistically different from that in bone marrow of B-ALL without PAX5 mutations, except for T follicular helper (Tfh) cells. But a variety of up-regulated immune inhibitory-related molecules in bone marrow of children's B- ALL with PAX5 mutations were identified. By different approaches, we found that several immune inhibitory-related molecules of CD8+ T cells in TME of PAX5 haplodeletion clones such as TIM3, NR4A1 and BATF, were increased significantly compared with that of PAX5 wild type control. The IFN-ɤ of CD8+ T cells in TME of PAX5 haplodeletion tumors was decreased significantly compared with that of PAX5 wild type control. Our study showed that PAX5 haploinsufficiency induced CD8+ T cells dysfunction or exhaustion by high expression of TIM3, NR4A1 and BATF in the CD8+ T cells of TME.
Abstract Outcomes for patients with relapsed and refractory (R/R) T‐cell acute lymphoblastic leukemia (T‐ALL) after allogeneic hematopoietic stem cell transplantation (allo‐HSCT) are dismal, with few available treatments. Recently, identification of cancer patients harboring neurotrophic tropomyosin receptor kinase (NTRK) gene fusions is constantly increasing, especially with the advent of NTRK inhibitors. However, the role of ETV6‐NTRK3 in T‐ALL has not been investigated. This case represented the first detailed report of T‐ALL patient harboring a cryptic ETV6‐NTRK3 fusion with an unfavorable prognosis, not only because of leukemia resistant to the standard multiagent chemotherapy but also early relapse after allo‐HSCT. Acquired EP300 mutation was found at relapse, which could explain the cause of recurrence and affect the follow‐up treatment. Combined targeted therapy like larotrectinib allied with pan‐targeted BCL‐2 inhibitor venetoclax, may be a potential maintenance treatment in R/R ETV6‐NTRK3 positive leukemia after allo‐HSCT. The leukemic clonal evolution might be revealed through transcriptome sequencing and overcome by drugs with universal targets. Our case demonstrated that both comprehensive profiling techniques (such as transcriptome sequencing, multiparameter flow cytometry, and digital droplet polymerase chain reaction) and a multimodality treatment strategy were critical for anticipating an early relapse and personalized therapy of R/R T‐cell leukemia.
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