Hematological Oncology最新文献

{"title":"Expression of “DNA damage response” pathway genes in diffuse large B-cell lymphoma: The potential for exploiting synthetic lethality","authors":"Adnan Mansoor,&nbsp;Hamza Kamran,&nbsp;Hassan Rizwan,&nbsp;Ariz Akhter,&nbsp;Tariq Mahmood Roshan,&nbsp;Meer-Taher Shabani-Rad,&nbsp;Prashant Bavi,&nbsp;Douglas Stewart","doi":"10.1002/hon.3225","DOIUrl":"10.1002/hon.3225","url":null,"abstract":"<p>Diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) are two of the most prevalent non-Hodgkin's lymphoma subtypes. Despite advances, treatment resistance and patient relapse remain challenging issues. Our study aimed to scrutinize gene expression distinctions between DLBCL and FL, employing a cohort of 53 DLBCL and 104 FL samples that underwent rigorous screening for genetic anomalies. The NanoString nCounter assay evaluated 730 cancer-associated genes, focusing on densely tumorous areas in diagnostic samples. Employing the Lymph2Cx method, we determined the cell-of-origin (COO) for DLBCL cases. Our meticulous analysis, facilitated by Qlucore Omics Explorer software, unveiled a substantial 37% of genes with significantly differential expression patterns between DLBCL and FL, pointing to nuanced mechanistic disparities. Investigating the impact of FL disease stage and DLBCL COO on gene expression yielded minimal differences, prompting us to direct our attention to consistently divergent genes in DLBCL. Intriguingly, our Gene Set Enrichment Analysis spotlighted 21% of these divergent genes, converging on the DNA damage response (DDR) pathway, vital for cell survival and cancer evolution. Strong positive correlations among most DDR genes were noted, with key genes like <i>BRCA1</i>, <i>FANCA</i>, <i>FEN1</i>, <i>PLOD1</i>, <i>PCNA</i>, and <i>RAD51</i> distinctly upregulated in DLBCL compared to FL and normal tissue controls. These findings were subsequently validated using RNA seq data on normal controls and DLBCL samples from public databases like The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) databases, enhancing the robustness of our results. Considering the established significance of these DDR genes in solid cancer therapies, our study underscores their potential applicability in DLBCL treatment strategies. In conclusion, our investigation highlights marked gene expression differences between DLBCL and FL, with particular emphasis on the essential DDR pathway. The identification of these DDR genes as potential therapeutic targets encourages further exploration of synthetic lethality-based approaches for managing DLBCL.</p>","PeriodicalId":12882,"journal":{"name":"Hematological Oncology","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2023-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hon.3225","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41134015","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to Prognostic impact of the UK Myeloma Research Alliance Risk Profile in transplant-ineligible patients with multiple myeloma who received a melphalan, prednisolone, and bortezomib regimen: A supplementary analysis of JCOG1105","authors":"","doi":"10.1002/hon.3226","DOIUrl":"10.1002/hon.3226","url":null,"abstract":"<p>Suzuki T, Maruyama D, Machida R, et al. Prognostic impact of the UK Myeloma Research Alliance Risk Profile in transplant-ineligible patients with multiple myeloma who received a melphalan, prednisolone, and bortezomib regimen: A supplementary analysis of JCOG1105. <i>Hematol Oncol.</i> 2023;41(3):590–593. https://doi.org/10.1002/hon.3103.</p><p>Subsequent to the publication of above article, the authors noted that the serum β2MG data (median level and unit) in Table 1 were incorrect. The correct median β2MG level is 3.1 (range, 1.4–14.3). The correct unit for β2MG is mg/L. This correction does not change the interpretation of the data or the overall conclusions of the study. The corrected Table 1 is shown below. The authors wish to apologize for any inconvenience caused.</p>","PeriodicalId":12882,"journal":{"name":"Hematological Oncology","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2023-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hon.3226","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41137512","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Refractory patients with favorable/intermediate-risk acute myeloid leukemia benefit from azacytidine maintenance therapy following allogeneic hematopoietic stem cell transplantation","authors":"Yigeng Cao,&nbsp;Xinhui Zheng,&nbsp;Haixiao Zhang,&nbsp;Mingyang Wang,&nbsp;Wenwen Guo,&nbsp;Xin Chen,&nbsp;Weihua Zhai,&nbsp;Jialin Wei,&nbsp;Donglin Yang,&nbsp;Yong Huang,&nbsp;Aiming Pang,&nbsp;Sizhou Feng,&nbsp;Erlie Jiang,&nbsp;Mingzhe Han","doi":"10.1002/hon.3232","DOIUrl":"10.1002/hon.3232","url":null,"abstract":"<p>Recurrence following allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the major cause of treatment failure in patients with myeloid malignancy. Azacytidine (AZA) maintenance is a promising therapy to prevent relapse and improve survival. We conducted a prospective, one-arm study involving 78 patients with myeloid malignancy at a high risk of recurrence who were enrolled between September 2019 and April 2022. Furthermore, 102 matched historical controls were selected using propensity score matching. With a median follow-up time of 19.6 (3.5–91.7) months, AZA maintenance therapy significantly improved relapse-free survival (RFS; log-rank test, <i>p</i> = 0.01). The AZA and control groups had a 1-year RFS of 87.7% (95% confidence interval [CI], 0.80–0.96) and 72.2% (95% CI, 0.64–0.82), respectively, with a hazard ratio (HR) of 0.21 (95% CI, 0.09–0. 47; <i>p</i> &lt; 0.01). There were no grade 4 adverse effects or deaths related to AZA. Refractory patients with favorable/intermediate-risk acute myeloid leukemia (AML) benefited more from AZA maintenance therapy than those with adverse-risk AML according to the European Leukemia Net guidelines (RFS in favorable/intermediate-risk AML, HR = 0.29, 95% CI, 0.11–0.79; RFS in adverse-risk AML, HR = 0.57, 95% CI, 0.21–1.6; <i>p</i> for interaction = 0.03). Our findings suggest that AZA maintenance therapy following allo-HSCT was safe and could reduce the incidence of relapse, particularly for refractory patients with favorable/intermediate-risk AML.</p>","PeriodicalId":12882,"journal":{"name":"Hematological Oncology","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2023-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41127683","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tislelizumab augment the efficacy of CD19/22 dual-targeted chimeric antigen receptor T cell in advanced stage relapsed or refractory B-cell non-Hodgkin lymphoma","authors":"Ying Zhang,&nbsp;Hongzhi Geng,&nbsp;Liangyu Zeng,&nbsp;Jiaqi Li,&nbsp;Qin Yang,&nbsp;Sixun Jia,&nbsp;Xiangping Zong,&nbsp;Wenzhi Cai,&nbsp;Shuangzhu Liu,&nbsp;Yutong Lu,&nbsp;Lei Yu,&nbsp;Caixia Li,&nbsp;Depei Wu","doi":"10.1002/hon.3227","DOIUrl":"10.1002/hon.3227","url":null,"abstract":"<p>Dual-targeted chimeric antigen receptor T (CAR-T) cell is an important strategy to improve the efficacy of CD19 CAR-T cell against refractory or relapsed B cell non-Hodgkin lymphoma (R/R B-NHL). However, durable responses are not achieved in most patients, in part owing CAR-T cell exhaustion caused by PD-1/PD-L1 pathway. We conducted a prospective, single-arm study of dual-targeted CD19/22 CAR-T cell combined with anti-PD-1 antibody, tislelizumab, in R/R B-NHL (NCT04539444). Tislelizumab was administrated on +1 day after patients received infusion of CD19/22 CAR-T cell. Responses, survival and safety were evaluated. From 1 August 2020 to 30 March 2023, 16 patients were enrolled. The median follow-up time is 16.0 (range: 5.0–32.0 months) months. Overall response was achieved in 14 of 16 (87.5%) patients, and the complete response (CR) was achieved in 11 of 16 (68.8%) patients. The 1-year progression-free survival and overall survival rates were 68.8% and 81.3%, respectively. Of the 14 patients responded, 9 patients maintained their response until the end of follow-up. Among the 15 out of 16 (93.8%) patients who had extranodal involvement, 14 (93.3%) patients achieved overall response rate with 11 (73.3%) patients achieving CR. Eight (50%) patients experienced cytokine release syndrome. No neurologic adverse events were reported. Gene Ontology-Biological Process enrichment analysis showed that immune response-related signaling pathways were enriched in CR patients. Our results suggest that CD19/22 CAR-T cell combined with tislelizumab elicit a safe and durable response in R/R B-NHL and may improve the prognosis of those patients.</p>","PeriodicalId":12882,"journal":{"name":"Hematological Oncology","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2023-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41153539","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Patients' preferences for chronic lymphocytic leukemia treatment: The CHOICE study","authors":"Paolo Sportoletti,&nbsp;Luca Laurenti,&nbsp;Annalisa Chiarenza,&nbsp;Gianluca Gaidano,&nbsp;Elisa Albi,&nbsp;Francesca Romana Mauro,&nbsp;Livio Trentin,&nbsp;Daniele Vallisa,&nbsp;Fabrizio Pane,&nbsp;Antonio Cuneo,&nbsp;Francesco Albano,&nbsp;Giulia Zamprogna,&nbsp;Marta Coscia,&nbsp;Alessandro Gozzetti,&nbsp;Gianluigi Reda,&nbsp;Morena Caira,&nbsp;Paola Finsinger,&nbsp;Giuliana Gualberti,&nbsp;Emilia Iannella,&nbsp;Simona Malgieri,&nbsp;Stefano Molica","doi":"10.1002/hon.3216","DOIUrl":"10.1002/hon.3216","url":null,"abstract":"<p>Chronic lymphocytic leukemia (CLL) therapies differ in efficacy, side effects, route, frequency, and duration of administration. We assessed patient preferences for treatment attributes and evaluated associations with disease stage, treatment line, and socio-demographic characteristics in a cross sectional, observational study conducted at 16 Italian hematology centers. Study visits occurred between February and July 2020; 401 adult patients with CLL (201 Watch and Wait (W&amp;W), 200 treated) participated in a discrete choice experiment (DCE), composed of 8 choices between pairs of treatment profiles with different levels of 5 attributes of currently available CLL treatments (length of response, route and duration of administration, risk of side effects including diarrhea, infections, or organ damage). Health-related quality of life was assessed with the EQ-5D-5L, EORTC QLQ-C30 and QLQ CLL-16. Previously treated patients had longer disease duration (7 vs. 5 years), higher prevalence of serious comorbidities (45.5% vs. 36.2%) and high-risk molecular markers (unmutated IGHV 55.6% vs. 17.1%; TP53 mutation 15.2% vs. 4.0%). Health-related quality of life scores were similar between groups. In the DCE, W&amp;W patients rated “possible occurrence of infections” highest (relative importance [RI] = 36.2%), followed by “treatment and relevant duration” (RI = 28.0%) and “progression-free survival (PFS)” (RI = 16.9%). Previously treated patients rated “treatment and relevant duration” highest (RI = 33.3%), followed by “possible occurrence of infections” (RI = 28.8%), “possible occurrence of organ damage” (RI = 19.4%), and “PFS” (RI = 9.8%). Concern over infection was rated highest overall; unexpectedly PFS was not among the most important criteria in either group, suggesting that the first COVID-19 pandemic wave may have influenced patient preferences and concerns about CLL therapy options.</p>","PeriodicalId":12882,"journal":{"name":"Hematological Oncology","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2023-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hon.3216","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41127537","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A short report of novel acute promyelocytic leukemia with runt-related transcription factor 1-retinoic acid receptor alpha","authors":"Xin Kong,&nbsp;Mingming Hu,&nbsp;Jian Zhang,&nbsp;Jingjing Han,&nbsp;Yin Liu,&nbsp;Baoquan Song,&nbsp;Zhihong Lin,&nbsp;Huiying Qiu","doi":"10.1002/hon.3214","DOIUrl":"10.1002/hon.3214","url":null,"abstract":"","PeriodicalId":12882,"journal":{"name":"Hematological Oncology","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2023-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41117752","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparison of autologous, matched sibling, and alternative donor stem cell transplant outcomes for acute myeloid leukemia patients in first remission: A propensity score matching study","authors":"Mingyang Wang,&nbsp;Haixiao Zhang,&nbsp;Xinhui Zheng,&nbsp;Jia Liu,&nbsp;Jiali Wang,&nbsp;Yigeng Cao,&nbsp;Xiaoyu Zhang,&nbsp;Rongli Zhang,&nbsp;Xin Chen,&nbsp;Weihua Zhai,&nbsp;Qiaoling Ma,&nbsp;Jialin Wei,&nbsp;Yong Huang,&nbsp;Donglin Yang,&nbsp;Yi He,&nbsp;Aiming Pang,&nbsp;Sizhou Feng,&nbsp;Mingzhe Han,&nbsp;Erlie Jiang","doi":"10.1002/hon.3230","DOIUrl":"10.1002/hon.3230","url":null,"abstract":"<p>Autologous hematopoietic stem cell transplantation (auto-HSCT), matched sibling donor HSCT (MSD-HSCT), and alternative donor HSCT (AD-HSCT) are viable post-remission treatment options for acute myeloid leukemia (AML). A total of 283 de novo favorable- and intermediate-risk AML patients, based on the ELN 2022 criteria, in first complete remission were initially included for propensity score matching. Following the matching process, 126 patients were selected for further analysis, with 42 patients in each of the auto-HSCT, MSD-HSCT, and AD-HSCT groups. Among the AD-HSCT group, 38 of 42 (90.5%) patients received haploidentical HSCT. In patients with persistent undetectable measurable residual disease (uMRD) before transplant (<i>n</i> = 83), overall survival (OS) was similar across the groups. However, auto-HSCT showed a trend of increased disease-free survival (DFS) compared to AD-HSCT (HR 2.85, <i>P</i> = 0.09), resulting in a 3-year DFS and OS of 79.1% and 82.8%, respectively. In the non-persistent uMRD group (<i>n</i> = 38), auto-HSCT exhibited a tendency to increase the risk of relapse, particularly when compared to AD-HSCT (HR 0.24, <i>P</i> = 0.07), but this did not result in inferior OS. The monthly direct medical cost per patient within the first 2 years after HSCT was significantly lower in auto-HSCT compared to MSD-HSCT (<i>P</i> = 0.015) and AD-HSCT (<i>P</i> &lt; 0.001). Our results provide evidence for the use of auto-HSCT as a viable therapeutic option for favorable- and intermediate-risk de novo AML patients in first complete remission with persistent uMRD. Additionally, our findings demonstrated a notable cost advantage associated with auto-HSCT compared to MSD-HSCT and AD-HSCT.</p>","PeriodicalId":12882,"journal":{"name":"Hematological Oncology","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2023-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41118984","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Venetoclax in biomarker-selected multiple myeloma patients: Impact of exposure on clinical efficacy and safety","authors":"Mohamed Badawi,&nbsp;Sheryl Coppola,&nbsp;Doerthe Eckert,&nbsp;Sathej Gopalakrishnan,&nbsp;Benjamin Engelhardt,&nbsp;Eva Doelger,&nbsp;Weize Huang,&nbsp;Edyta Dobkowska,&nbsp;Shaji Kumar,&nbsp;Rajeev M. Menon,&nbsp;Ahmed Hamed Salem","doi":"10.1002/hon.3222","DOIUrl":"10.1002/hon.3222","url":null,"abstract":"<p>Venetoclax, a potent BCL-2 inhibitor, is currently under development for treatment of t(11;14) Multiple myeloma (MM). The objective of this research was to investigate the exposure–response relationships of venetoclax for a phase 1/2 study evaluating venetoclax monotherapy or in combination with dexamethasone in relapsed or refractory MM. A total of 117 patients receiving venetoclax at 300, 600, 800, 900, or 1200 mg were included in the analysis. The impact of venetoclax exposures on efficacy (objective response rate [ORR], progression-free survival [PFS] and overall survival [OS]) as well as safety (treatment-emergent adverse effects (grade ≥3) of neutropenia, infection, and any grade of serious treatment-emergent adverse effects) was evaluated. In the t(11;14)-positive subpopulation, venetoclax exposure relationships to PFS and OS indicated a trend of longer PFS and OS with higher exposures. Moreover, logistic regression analyses for clinical response (ORR and ≥VGPR rate) demonstrated a statistically significant (<i>p</i> &lt; 0.05) relationship with exposure. Evaluation of the exposure-safety relationships demonstrated a lack of a relationship between venetoclax exposures (AUC_avg) and grade ≥3 infections, grade ≥3 neutropenia, grade ≥3 treatment-emergent adverse events or any grade serious treatment-emergent adverse events. These findings support further study of venetoclax at 800 mg QD dose in combination with dexamethasone in the t(11;14)-positive patient population where increased efficacy was observed without an increase in safety events.Clinical Trial: NCT01794520 registered 20 February 2013.</p>","PeriodicalId":12882,"journal":{"name":"Hematological Oncology","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2023-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41130320","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prognostic significance of the CFA ratio for newly diagnosed acute myeloid leukemia: A multicenter retrospective study","authors":"Takayuki Sakuma,&nbsp;Shin Fujisawa,&nbsp;Masatsugu Tanaka,&nbsp;Maki Hagihara,&nbsp;Hiroyuki Fujita,&nbsp;Katsumichi Fujimaki,&nbsp;Kengo Katsuki,&nbsp;Masahiro Akimoto,&nbsp;Marika Tanaka,&nbsp;Ayako Matsumura,&nbsp;Haruka Teshigawara,&nbsp;Taisei Suzuki,&nbsp;Hiroshi Teranaka,&nbsp;Yuki Nakajima,&nbsp;Takuya Miyazaki,&nbsp;Takayoshi Tachibana,&nbsp;Kenji Matsumoto,&nbsp;Rika Sakai,&nbsp;Heiwa Kanamori,&nbsp;Hideaki Nakajima","doi":"10.1002/hon.3228","DOIUrl":"10.1002/hon.3228","url":null,"abstract":"<p>The CFA ratio, calculated using pretreatment C-reactive protein (CRP), fibrinogen, and albumin levels (CRP × fibrinogen/albumin), was previously reported to be a significant prognostic factor for acute myeloid leukemia (AML). This multicenter retrospective study evaluated the prognostic value of the CFA ratio in 328 adult patients with newly diagnosed AML from April 2000 to March 2018. The median age was 49.5 years (range, 15–75 years), and 60.7% of the population were males. According to the European LeukemiaNet (ELN) risk classification, 67 patients (20.4%) were in the favorable-risk group, 197 patients (60.1%) in the intermediate-risk group, and 58 patients (17.7%) in the adverse-risk group. The median CFA ratio was 1.07 (0–67.69). Based on the calculated cutoff CFA ratio of 1.44, the cohort included 176 and 152 patients with low and high CFA ratios, respectively. At a median follow-up of 91.2 months, the 7-year overall survival (OS) and disease-free survival (DFS) rates were 51.2% and 48.6%, respectively, in the overall cohort. The 7-year OS rates were 61.7% and 39.0% in the low and high CFA ratio groups, respectively (<i>p</i> &lt; 0.001). The 7-year DFS rates were 58.1% and 37.0% in the low and high CFA ratio groups, respectively (<i>p</i> = 0.004). In univariate analysis, age ≥50 years, male sex, ELN risk class, and comorbidities were associated with poor OS. Age, ELN risk class, comorbidities, and high CFA ratio were associated with poor OS in multivariate analysis. Subgroup analysis revealed that the CFA ratio was significant in the intermediate and adverse ELN risk classes. These findings indicate the prognostic significance of the CFA ratio in AML.</p>","PeriodicalId":12882,"journal":{"name":"Hematological Oncology","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2023-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41121827","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Thymocyte selection-associated high mobility box protein regulates T lymphocytes exhaustion in patients with myelodysplastic syndromes by inhibiting PI3K/AKT/mTOR pathway","authors":"Haiyue Niu,&nbsp;Mengying Zhang,&nbsp;Mengyuan Liu,&nbsp;Liyan Yang,&nbsp;Liping Yang,&nbsp;Jie Ren,&nbsp;Yating Yu,&nbsp;Yumei Liu,&nbsp;Limin Xing,&nbsp;Zonghong Shao,&nbsp;Huaquan Wang","doi":"10.1002/hon.3224","DOIUrl":"10.1002/hon.3224","url":null,"abstract":"<p>Myelodysplastic syndromes (MDS) patients often experience CD8⁺T lymphocytes exhaustion, which plays a crucial role in the development of MDS. However, the specific role of thymocyte selection-associated high mobility box protein (TOX) in the CD8⁺T lymphocytes exhaustion in MDS patients remains unclear. In this study, we investigated the role of TOX in CD8⁺T lymphocytes exhaustion in patients with MDS. The expression of TOX, inhibitory receptors (IRs), and functional molecules in peripheral blood T lymphocytes of MDS patients and normal controls were detected using flow cytometry. Lentiviral transduction was used to create stable TOX-knockdown CD8⁺T lymphocytes, and small interfering RNA (si-RNA) was used to knock down TOX in Jurkat cells. The expression of TOX was found to be significantly higher in CD8⁺T lymphocytes of MDS patients compared to normal controls. This was associated with upregulated IRs and reduced expression of functional molecules such as Granzyme and Perforin. Myelodysplastic syndromes patients with higher TOX expression had poor clinical indicators and shorter survival. Knockdown of TOX using sh-RNA partially reverses the exhausted phenotype and enhances the lethality of CD8⁺T lymphocytes. Moreover, the knockdown of TOX using si-RNA in Jurkat cells improved cell proliferation activity, down-regulated IRs and activated PI3K/AKT/mTOR signaling pathway. TOX promotes the exhaustion of CD8⁺T lymphocytes by inhibiting PI3K/AKT/mTOR pathway, and targeted inhibition of TOX could partially restore the effector functions and activity of CD8⁺T lymphocytes.</p>","PeriodicalId":12882,"journal":{"name":"Hematological Oncology","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2023-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10247139","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}