Blood advances最新文献

{"title":"Intrathecal chemotherapy for ciltacabtagene autoleucel-associated movement and neurocognitive toxicity.","authors":"Kaitlin Kelly, Jennifer H Cooperrider, Michael R Bishop, Satyajit Kosuri, Andrzej Jakubowiak, Benjamin A Derman","doi":"10.1182/bloodadvances.2024015721","DOIUrl":"10.1182/bloodadvances.2024015721","url":null,"abstract":"","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":"3613-3616"},"PeriodicalIF":7.4,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12281119/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143976059","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Teclistamab for patients with heavily pretreated relapsed/refractory multiple myeloma and renal impairment.","authors":"Danai Dima, Aimaz Afrough, Utkarsh Goel, Ariel F Grajales-Cruz, Jack Khouri, Kelley Julian, Oren Pasvolsky, Rahul Banerjee, Beatrice Razzo, Christopher J Ferreri, Mariola A Vazquez-Martinez, James A Davis, Aishwarya Sannareddy, Omar Castaneda, Shahzad Raza, Andrew J Portuguese, Mahmoud R Gaballa, Masooma S Rana, Alex Lieberman-Cribbin, Shaun DeJarnette, Rebecca Gonzalez, Anna Chen, Megan M Herr, Lekha Mikkilineni, Hitomi Hosoya, Evguenia Ouchveridze, Gurbakhash Kaur, Adriana Rossi, Leyla Shune, Faiz Anwer, Yi Lin, Shambavi Richard, Douglas W Sborov, Rachid C Baz, Alfred L Garfall, Hans C Lee, Larry D Anderson, Andrew J Cowan, Krina K Patel, Peter M Voorhees, Surbhi Sidana, Doris K Hansen, Shebli Atrash, Sandra P Susanibar-Adaniya","doi":"10.1182/bloodadvances.2025016059","DOIUrl":"10.1182/bloodadvances.2025016059","url":null,"abstract":"<p><strong>Abstract: </strong>Outcomes of bispecific antibodies in patients with renal impairment (RI) are not well characterized, given the exclusion of these patients from clinical trials. Herein, we evaluated patients with relapsed/refractory multiple myeloma and RI treated with standard-of-care teclistamab. RI was defined as creatinine clearance (CrCl) <40 mL/min. CrCl <30 mL/min or dialysis dependence was defined as severe RI. Of the 384 included patients, 81 (21%) had RI, including 45 (18%) with severe RI, and 18 (5%) on dialysis. Patients with RI were more likely to be older (median age, 71 vs 67 years; P = .002) and have a higher median number of previous lines of therapy (7 vs 6; P = .04). Rates and severity of cytokine release syndrome (51% vs 59%; grade ≥3: 1.2% vs 1%) and immune effector cell-associated neurotoxicity syndrome (16% vs 13%; grade ≥3: 2.5% vs 2.6%) were similar in patients with and without RI, respectively. Patients with RI had higher baseline and day 30 post-teclistamab grade ≥3 anemia and grade ≥3 thrombocytopenia. Renal function did not worsen after teclistamab initiation in most patients with RI outside of the context of disease progression. Overall response rate (52% vs 56%; P = .61) and survival outcomes (median progression-free survival, 4.6 vs 6.5 months; P = .62) were comparable in patients with and without RI, respectively, after a median follow-up of 9.9 months. No differences in overall survival or non-relapse mortality were noted. Our findings suggest that treatment with teclistamab is feasible in patients with RI, including those on dialysis, with a similar safety and efficacy profile to patients without RI.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":"3408-3417"},"PeriodicalIF":7.4,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12274829/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143810606","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Belumosudil reduces oral chronic graft-versus-host disease tissue inflammation and fibrosis: a ROCKstar companion study.","authors":"Rubina Sharma, Noa G Holtzman, Iskra Pusic, Corey Cutler, Nathaniel Treister, Rohtesh S Mehta, Amin S Alousi, Nadarajah Vigneswaran, Ayesha Javaid, Francis Boksa, Drashty P Mody, Ana C Costa-da-Silva, Olivier Schueller, Sandrine Macé, Yu Yao, Ran Ji, Beifang Hu, Kathy Marshall, Bruce R Blazar, Stephanie J Lee, Steven Z Pavletic, Jacqueline W Mays","doi":"10.1182/bloodadvances.2025016170","DOIUrl":"10.1182/bloodadvances.2025016170","url":null,"abstract":"<p><strong>Abstract: </strong>Belumosudil (KD025), an oral, selective, Rho-associated, coiled-coil-containing protein kinase 2 (ROCK2) inhibitor, is approved for third-line treatment of chronic graft-versus-host disease (cGVHD). Previous studies demonstrated that ROCK2 inhibition reduces blood interleukin-17 (IL-17) activity and promotes regulatory T-cell (Treg cell) recovery. However, these studies did not evaluate immune responses within cGVHD-affected tissues. This study assessed tissue-level immune dynamics in 20 patients with oral cGVHD from the phase 2 ROCKstar trial, before and after 6 months of belumosudil treatment, focusing on key effector sites (oral mucosa [OM], minor salivary glands [MSGs], and skin) and the peripheral blood. After belumosudil treatment, reduction in collagen was observed in OM in parallel with decreased IL-17+ cell frequency in both OM (n = 14 pairs) and MSG (n = 11 pairs). IL-17 was primarily produced by non-T cells in the oral tissues. Immune cell frequencies in the OM decreased after treatment, whereas CD4 Treg cells increased in both the MSG and blood. Per overall or mouth-specific clinical response criteria, responders to belumosudil exhibited a reduction in collagen type I and IL-17 in the OM. Additionally, salivary transforming growth factor β1 (TGF-β1), a critical driver of fibrosis, decreased significantly, with a strong correlation observed between TGF-β1 and IL-17 levels. These findings illustrate the tissue-level response to belumosudil therapy and suggest that there is a reduction in tissue fibrosis and inflammation, thereby highlighting the therapeutic impact of ROCK2 inhibition in mitigating cGVHD. The ROCKstar study was registered at www.ClinicalTrials.gov as #NCT03640481.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":"3479-3494"},"PeriodicalIF":7.4,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12274834/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143976737","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"BMP-2 generates a functional bone marrow niche by inducing the differentiation of local mesenchymal cells into CAR cells.","authors":"Ikue Tosa, Mitsuaki Ono, Anh Tuan Dang, Ziyi Wang, Maiko Kimura, Wakana Kitagawa, Kei Ishibashi, Hang Thuy Do, Kun Zhao, Emilio Satoshi Hara, Noboru Asada, Takashi Nagasawa, Toshitaka Oohashi, Naoya Ohara, Takuo Kuboki","doi":"10.1182/bloodadvances.2024014062","DOIUrl":"10.1182/bloodadvances.2024014062","url":null,"abstract":"<p><strong>Abstract: </strong>Ectopic bone marrow (eBM) holds tremendous potential as an artificial organ, serving not only in stem cell transplantation therapies but also as a controlled experimental system for analyzing cellular dynamics and interactions between cells and the matrix during the formation, maintenance, and aging of BM. Although bone morphogenetic protein-2 (BMP-2) has been reported to induce eBM formation, it remains unproven whether BMP-2-induced eBM (BMP-eBM) can provide a functional BM niche that is comparable with native BM in long bones (LB-BM). In this study, through the use of single-cell RNA sequencing and transplantation models, we demonstrate that BMP-eBM displays a microstructure, cellular composition, and functional hematopoiesis similar to LB-BM. BMP-eBM establishes an optimized microenvironment capable of supporting hematopoietic stem cells and CXC chemokine ligand 12 (CXCL12)-abundant reticular (CAR) cells, which are critical components of the BM niche. BMP-eBM was able to significantly restore survival in irradiated mice. Through parabiosis and cell transplantation experiments, we identified that in situ adipose tissue-derived CD51highCxcl12-GFP- cells are the principal source of CAR cells within BMP-eBM. Furthermore, BMP-eBM can be isolated and after preconditioning, retransplanted as an independent, functional hematopoietic organ. In conclusion, our study confirms that BMP-eBM functions effectively as a hematopoietic organ, capable of supporting and maintaining a functional BM niche. These findings underscore BMP-2 as a crucial molecule for eBM generation and suggest its potential for addressing BM-related diseases and for use as a platform for in vitro and ex vivo biomedical applications.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":"3598-3612"},"PeriodicalIF":7.4,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12281123/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143623607","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An αIIbβ3 ligand-mimetic murine monoclonal antibody that produces platelet activation by engaging the FcγIIa receptor.","authors":"Jialing Wang, Lorena Buitrago, Lu Wang, Jihong Li, Thomas Walz, Barry S Coller","doi":"10.1182/bloodadvances.2024015368","DOIUrl":"10.1182/bloodadvances.2024015368","url":null,"abstract":"<p><strong>Abstract: </strong>To produce a murine monoclonal antibody (mAb) that binds to glycoprotein IIb/IIIa (αIIbβ3) and inhibits clot retraction (CR), we immunized mice with human platelets and tested hybridoma supernatants for their ability to bind to αIIbβ3 and inhibit CR. The immunoglobulin G1 (IgG1) mAb R6H8 completely inhibited CR at 20 μg/mL. Paradoxically, at 5 μg/mL, R6H8 initiated platelet aggregation and induced P-selectin expression, fibrinogen binding, and PAC-1 binding. At 20 μg/mL, however, R6H8 completely inhibited aggregation induced by thrombin PAR-1 receptor activating peptide SFLLRN (T6; 25 μg/mL) and T6-induced fibrinogen and PAC-1 binding to platelets. Platelet aggregation induced by R6H8 was inhibited by mAb IV.3, which blocks the FcγIIa receptor (FcγRIIa), and the Fab fragment of R6H8 did not induce platelet aggregation, suggesting that R6H8 binds to both αIIbβ3 and FcγRIIa. Cryogenic electron microscopy analysis of the R6H8 Fab-αIIbβ3 complex revealed that R6H8 (1) binds to the αIIbβ3 RGD binding pocket via an Arg-Tyr-Asp (RYD) sequence in its heavy chain complementarity-determining region 3; (2) interacts with β3 Asp126, producing a reorientation of Asp126 and loss of the adjacent to metal ion-dependent adhesion site Ca2+; and (3) initiates swing-out of the β3 hybrid domain. We conclude that R6H8 is an αIIbβ3 ligand-mimetic mAb that activates platelets via FcγRIIa at low concentrations and potently inhibits platelet aggregation and CR at high concentrations. R6H8 simulates the actions of a number of pathological antibodies, including platelet-activating antibodies developed after therapy with αIIbβ3 inhibitors and platelet-activating antibodies in heparin-induced thrombocytopenia and vaccine-induced immune thrombotic thrombocytopenia. As such, it may be a valuable reagent for better understanding these disorders and identifying potential therapies.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":"3518-3529"},"PeriodicalIF":7.4,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12274674/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143656222","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular profiling of primary renal marginal zone lymphoma reveals overlapping features with extranodal marginal zone lymphoma.","authors":"Axel Künstner, Vera von Kopylow, Philipp Lohneis, Matthias Kümmel, Hanno M Witte, Veronica Bernard, Stephanie Stölting, Kathrin Kusch, Sivahari Gorantla, Manuela Krokowski, Nikolas von Bubnoff, Hartmut Merz, Hauke Busch, Alfred C Feller, Niklas Gebauer","doi":"10.1182/bloodadvances.2025016263","DOIUrl":"10.1182/bloodadvances.2025016263","url":null,"abstract":"","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":"3658-3663"},"PeriodicalIF":7.4,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143965867","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Statin use and survival in CLL/SLL treated with ibrutinib: pooled analysis of 4 randomized controlled trials.","authors":"Ahmad Y Abuhelwa, Sara A Almansour, Jennifer R Brown, Humaid O Al-Shamsi, Ziad Abuhelwa, Zelal Kharaba, Yasser Bustanji, Mohammad H Semreen, Salma Ali, Ahmad Alhuraiji, Ross A McKinnon, Michael J Sorich, Karem H Alzoubi, Ashley M Hopkins","doi":"10.1182/bloodadvances.2024015287","DOIUrl":"10.1182/bloodadvances.2024015287","url":null,"abstract":"<p><strong>Abstract: </strong>Patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) have seen significant treatment advancements with the emergence of Bruton tyrosine kinase inhibitors like ibrutinib. Statin use has been linked to reduced mortality in several cancers, including CLL. However, their concomitant use with targeted therapies such as ibrutinib remains unexplored. This study investigates the association of statin use with survival and adverse event outcomes in patients with CLL/SLL initiating contemporary treatment regimens, including ibrutinib. Individual participant data from 4 randomized trials-RESONATE, RESONATE-2, iLLUMINATE, and HELIOS-were used. Associations between baseline statin use and treatment outcomes were examined using Cox proportional hazards models for overall survival (OS), progression-free survival (PFS), and cancer-specific survival (CCS), and logistic regression models for grade ≥3 adverse effects. Analyses were adjusted for age, sex, weight, Eastern Cooperative Oncology Group performance status, disease diagnosis, bulky disease (≥5 cm), time since diagnosis, comorbidity count, and the use of beta-blockers, calcium channel blockers, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, and diuretics. Of 1467 patients, 424 (29%) were using statins. Statin use was significantly associated with improved OS (adjusted hazard ratio [aHR] 0.62 [95% CI, 0.48‑0.79], P < 0.001), PFS (aHR 0.74 [95% CI, 0.62-0.89], P = 0.001), and CCS (aHR 0.39 [95% CI, 0.22-0.70], P = 0.001). Findings were consistent across ibrutinib vs nonibrutinib treatment arms and CLL vs SLL diagnosis. No significant association with grade ≥3 adverse effects was observed. Statin use was identified as an independent positive prognostic factor in patients with CLL/SLL, irrespective of the treatment employed. Further research is needed to validate these results and explore the underlying impacts of statins in CLL/SLL. These trials were registered at www.ClinicalTrials.gov as #NCT01578707, #NCT01722487, #NCT02264574, and #NCT01611090.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":"3566-3575"},"PeriodicalIF":7.4,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12275193/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143977213","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High rate of complete responses induced by platinum-based regimen with BTK inhibitors in Richter syndrome.","authors":"Georgios Pongas, Maryam Alasfour, Daniel P Cassidy, Juan P Alderuccio, Joseph D Rosenblatt, Izidore S Lossos","doi":"10.1182/bloodadvances.2025015913","DOIUrl":"10.1182/bloodadvances.2025015913","url":null,"abstract":"","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":"3594-3597"},"PeriodicalIF":7.4,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12281164/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143976740","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterization and prediction of hematotoxicity in pediatric patients receiving tisagenlecuecel.","authors":"Swati Naik, Subodh Selukar, Aimee C Talleur, Samira Deshpande, Gabriela Llaurador Caraballo, Vanessa A Fabrizio, Rayne H Rouce, Xiaopei Lily Zeng, Anant Vatsayan, Jenna Rossoff, Holly L Pacenta, Samuel John, Christine L Phillips, Julie-An M Talano, Amy Moskop, Michael R Verneris, Gary Douglas Myers, Erin M Hall, Nicole A Karras, Challice L Bonifant, Muna Qayed, Emily Bakinowski, Amy Keating, Susanne H C Baumeister, Emily Tomilson, Michelle L Hermiston, Prakash Satwani, Christa Krupski, Vasant Chinnabhandar, Heather E Stefanski, Emily Egeler, Kevin J Curran, Theodore W Laetsch, Crystal L Mackall, Snehit Prabhu, Khanh Nguyen, Christina Baggott, Liora M Schultz, Kevin O McNerney","doi":"10.1182/bloodadvances.2025016824","DOIUrl":"https://doi.org/10.1182/bloodadvances.2025016824","url":null,"abstract":"<p><p>Hematotoxicity is the most frequent severe toxicity following chimeric antigen receptor (CAR) T therapy. However, limited data exist on risk factors and outcomes for hematotoxicity for children and young adults (CAYA) with B-acute lymphoblastic leukemia (B-ALL) treated with tisagenlecleucel. We conducted a multi-institutional study involving 326 CAYA, with 144 evaluable in an initial training cohort and 141 evaluable in a validation cohort, through the Pediatric Real World CAR Consortium to characterize the incidence and outcomes of prolonged severe neutropenia (PSN) and to develop a predictive risk score for PSN, tailored for use in this population. The incidence of PSN, defined as an absolute neutrophil count (ANC) of <500 cells/µL for ≥ 30 days, was 15.3% in the initial training cohort and 21% in the validation cohort. Development of PSN was associated with inferior overall survival (p<0.001), relapse-free survival (p=0.01), higher non-relapse mortality (p=0.003), and a greater risk of infections within 30 days (p=0.03). Multivariable penalized regression analysis identified key risk factors for PSN which included pre-infusion C-reactive protein and bone marrow disease burden, and post-infusion peak ferritin and occurrence of severe CRS, which were used to create the CytoRisk score. In the validation cohort, the CytoRisk score discriminated between patients with and without PSN (area under the curve: 0.90, specificity: 93%, sensitivity: 71%, positive predictive value: 74%, negative predictive value: 92%). The CytoRisk score may be used to a priori identify patients at highest risk of PSN and overall worse outcomes.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144681973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"YX0798 Is a Highly Potent, Selective, and Orally Effective CDK9 Inhibitor for Treating Aggressive Lymphoma.","authors":"Vivian Jiang, Yu Xue, Hong Kim, Qingsong Cai, Tianci Zhang, Lei Nie, Joseph McIntosh, Yang Liu, Haiying Chen, Jia Zhou, Michael L Wang","doi":"10.1182/bloodadvances.2025016511","DOIUrl":"https://doi.org/10.1182/bloodadvances.2025016511","url":null,"abstract":"<p><p>Non-genetic transcription evolution has been increasingly explored and recognized to drive tumor cell progression and therapeutic resistance. As the regulation hub of transcription machinery, cyclin-dependent kinase 9 (CDK9) is the gatekeeper of RNA polymerase II (Pol II) transcription, and CDK9 dysfunction results in transcriptomic reprogramming and tumor cell progression. We recently reported that the HSP90-MYC-CDK9 network drives therapeutic resistance in mantle cell lymphoma (MCL) through transcriptomic reprogramming. We also showed that targeting CDK9 by AZD4573 and enitociclib is a safe and effective treatment in preclinical MCL models, supporting CDK9 as a valid therapeutic target for MCL. However, current CDK9 inhibitors (CDK9i) under therapeutic development have room for improvement due to limited target selectivity and oral bioavailability. To this end, YX0798 was discovered to be a novel CDK9i through structural optimization. YX0798 demonstrated remarkable target selectivity and high affinity in binding to CDK9. Furthermore, YX0798 showed good oral bioavailability. YX0798, when administrated orally (5 mg/kg, daily), led to an efficacious anti-tumor activity in vivo and showed the potency in overcoming therapeutic resistance. Mechanistically, YX0798 downregulated the short-lived oncoprotein c-MYC and pro-survival protein MCL-1 as a common mechanism of CDK9 inhibition. Moreover, YX0798 disrupted the cell cycle and resulted in transcriptomic reprogramming, eventually leading to cell death. Furthermore, YX0798 has the potential to be used in combination therapy with clinical agents to improve treatment efficacy. Together, these data demonstrate that YX0798 has oral bioavailability, exquisite selectivity, and anti-tumor potency that results from driving transcription reprogramming towards tumor cell killing.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144681976","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}