Blood Neoplasia最新文献

{"title":"Single-cell sequencing reveals shared clonal signatures in nonmalignant B and tumor cells in T-prolymphocytic leukemia","authors":"Caroline Hesselager ,&nbsp;Ingrid Thörn ,&nbsp;Millaray Marincevic ,&nbsp;Claes Ladenvall ,&nbsp;Jonas Almlöf ,&nbsp;Sara Löfgren ,&nbsp;Simone Weström ,&nbsp;Helena Nord ,&nbsp;Lesley-Ann Sutton ,&nbsp;Lucia Cavelier ,&nbsp;Panagiotis Baliakas ,&nbsp;Rose-Marie Amini","doi":"10.1016/j.bneo.2025.100076","DOIUrl":"10.1016/j.bneo.2025.100076","url":null,"abstract":"<div><h3>Abstract</h3><div>This study aimed to elucidate the clonal origin and evolutionary dynamics of T-cell prolymphocytic leukemia (T-PLL) using targeted next generation sequencing (NGS) of paired samples from diagnosis and relapse. DNA from both nonmalignant and tumor cells was extracted from sorted cell fractions obtained from 16 patients with T-PLL. NGS was performed using a customized Haloplex gene panel comprising 19 genes recurrently mutated in T-PLL (<em>ATM</em> and <em>JAK/STAT</em> pathway). Droplet digital polymerase chain reaction was performed to confirm mutations detected by NGS with low variant allele frequencies. Single-cell analysis of genomic DNA combined with cell surface protein markers was performed using the Mission Bio Tapestri Platform. The most frequently mutated gene was <em>ATM</em> (n = 10) followed by <em>STAT5B</em> (n = 7), <em>JAK3</em> (n = 3), <em>EZH2</em> (n = 3), <em>BCOR</em> (n = 1), and <em>STAT6</em> (n = 1). Relapse samples were available for 9 of the 16 patients. Varying patterns of clonal shifts were observed between diagnosis and relapse (increase, decrease, both increase and decrease, and no change). The presence of pathogenic variants in <em>ATM</em>, <em>EZH2</em>, <em>STAT5B</em>, and <em>JAK3</em> in both normal sorted B cells and clonal T cells was confirmed. Single-cell analysis revealed shared mutations in both nonmalignant B and clonal T cells in 1 case. A pathogenic variant within the <em>ATM</em> gene of potential germ line origin was observed in 1 case. T-PLL exhibits variable patterns of clonal evolution between diagnosis and relapse. Single-cell multiomics analysis reveals shared mutational signatures in both nonmalignant B cells and clonal T cells. The role of germ line <em>ATM</em> mutations in the pathogenesis of T-PLL should be further explored.</div></div>","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":"2 2","pages":"Article 100076"},"PeriodicalIF":0.0,"publicationDate":"2025-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143696874","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prognostic impact of RDI of vincristine in patients with DLBCL receiving R-CHOP: a supplementary analysis of JCOG0601","authors":"Takahiro Nakashima ,&nbsp;Tomotaka Suzuki ,&nbsp;Ryunosuke Machida ,&nbsp;Kazuyuki Shimada ,&nbsp;Tsutomu Kobayashi ,&nbsp;Dai Maruyama ,&nbsp;Wataru Munakata ,&nbsp;Shinsuke Iida ,&nbsp;Ken Ohmachi ,&nbsp;Tomohiro Kinoshita ,&nbsp;Kiyoshi Ando ,&nbsp;Hirokazu Nagai","doi":"10.1016/j.bneo.2025.100077","DOIUrl":"10.1016/j.bneo.2025.100077","url":null,"abstract":"<div><h3>Abstract</h3><div>R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine [VCR], and prednisolone) is the standard of care for previously untreated patients with diffuse large B-cell lymphoma (DLBCL). However, some DLBCL survivors experience long-lasting VCR-related peripheral neuropathy (PN). VCR dose is usually reduced based on PN severity, but inconsistent results have been reported regarding the effect of VCR dose reduction on the prognosis of patients with DLBCL. To evaluate the clinical impact of the relative dose intensity (RDI) of VCR (RDI_O), we conducted a supplementary analysis of JCOG0601, a randomized phase 2/3 trial in which R-CHOP and CHOP with 8 doses of weekly rituximab were compared for progression-free survival (PFS). Among 422 patients enrolled in JCOG0601, 401 who had received at least 6 courses of protocol treatment were eligible. PFS was not significantly different between patients with low RDI_O (&lt;95% [n = 161]) and high RDI_O (≥95% [n = 240]; <em>P</em> = .0679), although those with low RDI_O tended to have poor PFS (3-year PFS, 83.7% vs 78.2%). Multivariable analysis revealed that the presence of B symptoms and high-intermediate or high International Prognostic Index (IPI) risk, but not RDI_O, were associated with poor PFS. To our knowledge, this is the first study revealing VCR dose reduction may not be associated with poor PFS as much as the presence of B symptoms and high-intermediate or high IPI risk, using data from a prospective trial with rituximab plus 21-day cycles of CHOP. If the patients with DLBCL can complete rituximab plus CHOP treatment, VCR dose reduction due to toxicity may not significantly impair treatment efficacy. JCOG0601 was registered at <span><span>www.jcog.jp/en/trials</span><svg><path></path></svg></span> as #jRCTs031180139.</div></div>","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":"2 2","pages":"Article 100077"},"PeriodicalIF":0.0,"publicationDate":"2025-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143696873","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Safety landscape of bispecific antibody therapy in non-Hodgkin lymphoma: a meta-analysis","authors":"Rodrigo Fonseca ,&nbsp;Alex J. Liu ,&nbsp;Blake T. Langlais ,&nbsp;Diana Almader-Douglas ,&nbsp;Holenarasipur R. Vikram ,&nbsp;Talal Hilal","doi":"10.1016/j.bneo.2024.100061","DOIUrl":"10.1016/j.bneo.2024.100061","url":null,"abstract":"<div><h3>Abstract</h3><div>Bispecific antibodies (BsAbs) have emerged as a novel immunotherapy option for the treatment of non-Hodgkin lymphoma; however; their safety profiles remain underexplored. We conducted a systematic review and meta-analysis to better delineate the safety profiles of BsAbs, focusing on the prevalence and rates of infection, neutropenia, cytokine release syndrome (CRS), and immune effector cell–associated neurotoxicity syndrome (ICANS). A comprehensive literature search led to the inclusion of 32 trials, with a total of 2192 patients. Median age of participants was 66 years (range, 55-84) with a median of 2 prior lines of therapy (range, 0-5). At a median follow-up of 9.4 months (range, 2.8-32 , the pooled prevalence of all-grade and grade ≥3 neutropenia was 38% and 26%, respectively, with all-grade and grade ≥3 infections occurring at a rate of 38% and 12%, respectively. The prevalence of all grade CRS was 48% but only 2% was grade ≥3, whereas ICANS was infrequent (5% all grade). Stratification revealed both increased all-grade neutropenia and infection rates with combination therapy in comparison to BsAbs monotherapy. Despite these variations, BsAbs demonstrated an overall manageable safety profile, suggesting their viability as a treatment option in the relapsed/refractory setting. Standardized safety reporting and vigilant monitoring are essential to optimize their clinical use and improve patient outcomes.</div></div>","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":"2 1","pages":"Article 100061"},"PeriodicalIF":0.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143149981","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Real-world safety profile of therapy with ibrutinib or acalabrutinib in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma","authors":"Ramsay Hafer ,&nbsp;Francesco Iadevaia ,&nbsp;Thomas Z. Rohan ,&nbsp;Teresa Duong ,&nbsp;Maria Poluch ,&nbsp;Gina Keiffer ,&nbsp;Michael Li ,&nbsp;Andres Ferber ,&nbsp;Luca Laurenti ,&nbsp;Alan S. Khoo ,&nbsp;Pierluigi Porcu","doi":"10.1016/j.bneo.2024.100064","DOIUrl":"10.1016/j.bneo.2024.100064","url":null,"abstract":"","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":"2 1","pages":"Article 100064"},"PeriodicalIF":0.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143150034","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enitociclib, a selective CDK9 inhibitor: in vitro and in vivo preclinical studies in multiple myeloma","authors":"Son Tran ,&nbsp;Patrick Sipila ,&nbsp;Melanie M. Frigault ,&nbsp;Beatrix Stelte-Ludwig ,&nbsp;Amy J. Johnson ,&nbsp;Joseph Birkett ,&nbsp;Raquel Izumi ,&nbsp;Ahmed Hamdy ,&nbsp;Ranjan Maity ,&nbsp;Nizar J. Bahlis ,&nbsp;Paola Neri ,&nbsp;Aru Narendran","doi":"10.1016/j.bneo.2024.100050","DOIUrl":"10.1016/j.bneo.2024.100050","url":null,"abstract":"<div><h3>Abstract</h3><div>Multiple myeloma (MM) is a cancer of plasma cells that remains incurable despite advances in treatment options. In this study, a library of 216 clinically feasible small-molecule inhibitors was screened to identify agents that selectively inhibit MM cell proliferation. Enitociclib, a cyclin-dependent kinase 9–specific small-molecule inhibitor, was found to be highly effective in decreasing cell viability and inducing apoptosis in 4 MM cell lines. Enitociclib inhibited the phosphorylation of the carboxy-terminal domain (CTD) of RNA polymerase II at Ser2/Ser5 and repressed the protein expression of oncogenes c-Myc, myeloid cell leukemia-1 (Mcl-1), and proliferating cell nuclear antigen (PCNA) in MM cells. Additionally, enitociclib demonstrated synergistic effects with several anti-MM agents, including bortezomib, lenalidomide, pomalidomide, and venetoclax. These results suggest that enitociclib may represent a promising therapeutic option for the treatment of MM, either as a single agent or in combination with other anti-MM agents.</div></div>","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":"2 1","pages":"Article 100050"},"PeriodicalIF":0.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143150205","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aberrant heterochromatin silences immune response genes in chronic lymphocytic leukemia","authors":"Olivia M. Depies ,&nbsp;Qianqian Guo ,&nbsp;Yuan Gao ,&nbsp;Sutapa Sinha ,&nbsp;Zhenqing Ye ,&nbsp;Weiguo Han ,&nbsp;Kari G. Rabe ,&nbsp;Mingma S. Hoel ,&nbsp;Heather C. Darby ,&nbsp;Chuanhe Yu ,&nbsp;Esteban Braggio ,&nbsp;Sameer A. Parikh ,&nbsp;Susan L. Slager ,&nbsp;Neil E. Kay ,&nbsp;Zhiquan Wang","doi":"10.1016/j.bneo.2024.100059","DOIUrl":"10.1016/j.bneo.2024.100059","url":null,"abstract":"<div><h3>Abstract</h3><div>Epigenetic alterations have been found in chronic lymphocytic leukemia (CLL), but the functional importance of these changes remains underexplored. Here, we characterized the genome-wide histone modification landscapes of CLL using patient-derived samples across the disease course. Compared with normal B cells, we found that the enhancers specifically lost in CLL B cells are associated with the downregulation of genes involved in immune response. Importantly, these lost enhancers exhibit an increased level of heterochromatin marks, including H3K9me3 and H3K27me3. Using the <em>EBF1</em> gene locus as an example, we demonstrated that acquired H3K9me3 contributes to enhancer silencing and associated gene suppression. We further found that this aberrant chromatin signature also exists in the CLL precursor stage monoclonal B-cell lymphocytosis (MBL) cells, implicating the importance of epigenetic silencing in CLL evolution. Finally, when treated with the Bruton tyrosine kinase inhibitor ibrutinib, these silenced enhancers are relatively stable during therapy compared with the CLL-gained enhancers. In summary, we described an epigenetic silencing mechanism mediated by the heterochromatin that persists throughout CLL disease development and treatment and which may increase the risk of severe infections in MBL and CLL.</div></div>","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":"2 1","pages":"Article 100059"},"PeriodicalIF":0.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143150073","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Outcomes of follicular lymphoma with leukemic phase in the modern era: results from a large multicenter study","authors":"Asaad Trabolsi ,&nbsp;Sunwoo Han ,&nbsp;Narendranath Epperla ,&nbsp;Kaitlin Annunzio ,&nbsp;Firas Baidoun ,&nbsp;Muhamad Alhaj Moustafa ,&nbsp;Dan Morgenstern-Kaplan ,&nbsp;Peter Doukas ,&nbsp;Frederique St-Pierre ,&nbsp;Brittany McCall ,&nbsp;Lindsey Fitzgerald ,&nbsp;Jose Sandoval-Sus ,&nbsp;Shivani Dalal ,&nbsp;Isildinha M. Reis ,&nbsp;Jennifer Rose Chapman-Fredricks ,&nbsp;Seo-Hyun Kim ,&nbsp;Cherry Au ,&nbsp;Natalie B. Otto ,&nbsp;Khaled Alhamad ,&nbsp;Thomas Ollila ,&nbsp;Juan Pablo Alderuccio ∗","doi":"10.1016/j.bneo.2024.100063","DOIUrl":"10.1016/j.bneo.2024.100063","url":null,"abstract":"","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":"2 1","pages":"Article 100063"},"PeriodicalIF":0.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143192998","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A phase 1 study of interleukin-15 in combination with mogamulizumab in relapsed and refractory T-cell malignancies","authors":"Max J. Gordon ∗ ,&nbsp;Sigrid Dubois ∗ ,&nbsp;Milos D. Miljkovic ,&nbsp;Samuel Ng ,&nbsp;Bonita Bryant ,&nbsp;Rahul Lakhotia ,&nbsp;Christopher Melani ,&nbsp;Stefania Pittaluga ,&nbsp;Kevin Conlon ,&nbsp;Thomas Waldmann ,&nbsp;Louis M. Staudt ,&nbsp;Wyndham H. Wilson ,&nbsp;Mark Roschewski","doi":"10.1016/j.bneo.2024.100054","DOIUrl":"10.1016/j.bneo.2024.100054","url":null,"abstract":"<div><h3>Abstract</h3><div>Recombinant human interleukin-15 (rhIL-15) is an immunotherapeutic agent that enhances natural killer (NK) cells to augment the antibody-dependent cellular cytotoxicity (ADCC) of monoclonal antibodies. Mogamulizumab is a CC chemokine receptor 4–directed monoclonal antibody that exerts cytotoxicity through ADCC and depletes regulatory T cells within the tumor microenvironment. We conducted a phase 1 clinical trial of rhIL-15 in combination with mogamulizumab. Patients with relapsed or refractory adult T-cell leukemia/lymphoma (ATLL), mycosis fungoides (MF), and Sezary syndrome (SS) received a fixed dose mogamulizumab, combined with escalating doses of rhIL-15 to identify the maximum tolerated dose (MTD). Six patients were enrolled, 4 with ATLL and 2 with MF/SS. The most common adverse events were rash, infection, and fever (67% of all). Two patients (33%) had grade 4 acute kidney injury, and in 25% of cycles, grade 3 or higher anemia was present. The MTD was dose level 1. One patient with ATLL had a partial response despite receiving only 4 cycles because of grade 4 myositis. Circulating NK cells were increased in all patients during the first cycle and a rapid reduction in tumor cells within the peripheral circulation was noted. Ex vivo assessment demonstrated increased NK cell activation and increased cell lysis in the presence of monoclonal antibodies after only 5 days. Our small study suggests that rhIL-15, in combination with mogamulizumab, leads to effector NK cell activation and regulatory T-cell depletion but has an unfavorable safety profile. Future development of combinations of immunotherapy that target the microenvironment in relapsed or refractory T-cell lymphomas remains rational. This trial was registered at <span><span>www.ClinicalTrials.gov</span><svg><path></path></svg></span> as #NCT04185220.</div></div>","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":"2 1","pages":"Article 100054"},"PeriodicalIF":0.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143149220","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"JAK1/2 inhibitor ruxolitinib for the treatment of systemic chronic active Epstein-Barr virus disease: a phase 2 study","authors":"Yu Uemura ,&nbsp;Masahide Yamamoto ,&nbsp;Masataka Ishimura ,&nbsp;Hirokazu Kanegane ,&nbsp;Akihisa Sawada ,&nbsp;Akihiro Hirakawa ,&nbsp;Ken-Ichi Imadome ,&nbsp;Mayumi Yoshimori ,&nbsp;Masashi Nagata ,&nbsp;Kouhei Yamamoto ,&nbsp;Norio Shimizu ,&nbsp;Ryuji Koike ,&nbsp;Ayako Arai","doi":"10.1016/j.bneo.2024.100053","DOIUrl":"10.1016/j.bneo.2024.100053","url":null,"abstract":"<div><h3>Abstract</h3><div>Systemic chronic active Epstein-Barr virus disease (sCAEBV) is a rare intractable EBV-positive T-cell or natural killer (NK)-cell lymphoid neoplasm with systemic inflammation. The only curative treatment is allogeneic hematopoietic stem cell transplantation (allo-HSCT). Disease activity defined by multiple inflammatory symptoms is associated with poor survival. In sCAEBV, signal transducer and activator of transcription 3 (STAT3) is constitutively activated in EBV-infected T and NK cells and promotes their activation and survival. Ruxolitinib, a Janus kinase 1/2 inhibitor, suppresses the STAT3 activation in vitro, suggesting its clinical potential. We conducted a phase 2, multicenter, open-label study to investigate the effects of ruxolitinib on disease activity of sCAEBV. Complete response (CR) and partial response were defined as complete and partial resolution of disease activity, respectively. Nine patients received ruxolitinib, and 7 patients completed the study. The primary end point, CR rate (%) 56 days after the administration or at early termination as defined in the protocol, was 22.2% (2/9). No patient showed hematopoietic toxicity nor disease progression. Notably, 71.4% (5/7) of patients who completed the study were treated at our outpatient clinic. One patient developed a severe adverse event of oral bleeding due to lesion shrinkage during the treatment, and ruxolitinib was discontinued. EBV-DNA levels in whole blood did not change significantly whether the treatment was effective or not. After ruxolitinib treatment, 7 patients received allo-HSCT, and 5 of them achieved CR with undetectable EBV-DNA levels in whole blood. Ruxolitinib is a potent treatment drug that may improve allo-HSCT outcomes by suppressing disease activity of sCAEBV. The trial was registered at University hospital Medical Information Network (UMIN), numbered UMIN000035121.</div></div>","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":"2 1","pages":"Article 100053"},"PeriodicalIF":0.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143149222","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Loss of p53 impairs death receptor expression and confers resistance to CD19 CAR T-cell therapy in BCP-ALL","authors":"Willem P. J. Cox ∗ ,&nbsp;Noël M. M. Dautzenberg ∗ ,&nbsp;Linde Dekker ,&nbsp;Tesa Klenovsek ,&nbsp;Annelisa M. Cornel ,&nbsp;Marliek van Hoesel ,&nbsp;Dorette S. van Ingen Schenau ,&nbsp;Reno S. Bladergroen ,&nbsp;Roland P. Kuiper ,&nbsp;Laurens T. van der Meer ,&nbsp;Friso G. Calkoen † ,&nbsp;Stefan Nierkens † ,&nbsp;Frank N. van Leeuwen †","doi":"10.1016/j.bneo.2024.100060","DOIUrl":"10.1016/j.bneo.2024.100060","url":null,"abstract":"<div><h3>Abstract</h3><div>Loss of p53 function predicts a dismal outcome in relapsed B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Chimeric antigen receptor T-cell (CAR T) therapy was recently approved to salvage relapsed/refractory BCP-ALL. We observed a significantly worse overall survival after CD19-targeting CAR T therapy in children with <em>TP53</em>-mutated (<em>TP53</em>^Mut) compared with <em>TP53</em>–wild-type (<em>TP53</em>^WT) BCP-ALL. To investigate the effect of p53 loss on CAR T therapy response, we modeled <em>TP53</em> mutations in 2 BCP-ALL cell lines and observed resistance to CAR T upon p53 loss. Moreover, expression analysis in cell lines and xenografts demonstrated that loss of p53 abrogates the expression of the death receptors Fas and death receptor 5 (DR5), both implicated in CAR T cytotoxicity. Conversely, ectopic expression of Fas improved CAR T cytotoxicity. Furthermore, p53 stabilization induced expression of both Fas and DR5, accompanied by increased CAR T–mediated killing. Although these findings provide mechanistic insight into why CAR T therapy fails against <em>TP53</em>^Mut BCP-ALL, they may also provide opportunities to enhance the efficacy of CAR T treatment both in patients with <em>TP53</em>^Mut and <em>TP53</em>^WT BCP-ALL. Furthermore, these data underscore the need for alternative curative therapies for this very high-risk patient group.</div></div>","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":"2 1","pages":"Article 100060"},"PeriodicalIF":0.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143150203","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}