Blood最新文献

{"title":"Broken brakes: PRC loss foils menin inhibition.","authors":"Nahal Azimi, Aniruddha J Deshpande","doi":"10.1182/blood.2024026297","DOIUrl":"10.1182/blood.2024026297","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"144 19","pages":"1979-1980"},"PeriodicalIF":21.0,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11561538/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142603145","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":"The promise of allosteric kinase inhibition.","authors":"Neil P Shah","doi":"10.1182/blood.2024026052","DOIUrl":"https://doi.org/10.1182/blood.2024026052","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"144 19","pages":"1975-1976"},"PeriodicalIF":21.0,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142603205","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":"NG2 is a target gene of MLL-AF4 and underlies glucocorticoid resistance in MLLr B-ALL by regulating NR3C1 expression.","authors":"Belén Lopez-Millan, Alba Rubio-Gayarre, Meritxell Vinyoles, Juan L Trincado, Mario F Fraga, Narcís Fernandez-Fuentes, Mercedes Guerrero-Murillo, Alba Martinez, Talia Velasco-Hernandez, Aïda Falgàs, Carla Panisello, Gemma Valcarcel, José Luis Sardina, Paula López-Martí, Biola M Javierre, Beatriz Del Valle-Pérez, Antonio García de Herreros, Franco Locatelli, Rob Pieters, Michela Bardini, Giovanni Cazzaniga, Juan Carlos Rodríguez-Manzaneque, Thomas Hanewald, Rolf Marschalek, Thomas A Milne, Ronald W Stam, Juan Ramón Tejedor, Pablo Menendez, Clara Bueno","doi":"10.1182/blood.2023022050","DOIUrl":"10.1182/blood.2023022050","url":null,"abstract":"<p><strong>Abstract: </strong>B-cell acute lymphoblastic leukemia (B-ALL) is the most common pediatric cancer, with long-term overall survival rates of ∼85%. However, B-ALL harboring rearrangements of the MLL gene (also known as KMT2A), referred to as MLLr B-ALL, is common in infants and is associated with poor 5-year survival, relapses, and refractoriness to glucocorticoids (GCs). GCs are an essential part of the treatment backbone for B-ALL, and GC resistance is a major clinical predictor of poor outcome. Elucidating the mechanisms of GC resistance in MLLr B-ALL is, therefore, critical to guide therapeutic strategies that deepen the response after induction therapy. Neuron-glial antigen-2 (NG2) expression is a hallmark of MLLr B-ALL and is minimally expressed in healthy hematopoietic cells. We recently reported that NG2 expression is associated with poor prognosis in MLLr B-ALL. Despite its contribution to MLLr B-ALL pathogenesis, the role of NG2 in MLLr-mediated leukemogenesis/chemoresistance remains elusive. Here, we show that NG2 is an epigenetically regulated direct target gene of the leukemic MLL-ALF transcription elongation factor 4 (AF4) fusion protein. NG2 negatively regulates the expression of the GC receptor nuclear receptor subfamily 3 group C member 1 (NR3C1) and confers GC resistance to MLLr B-ALL cells. Mechanistically, NG2 interacts with FLT3 to render ligand-independent activation of FLT3 signaling (a hallmark of MLLr B-ALL) and downregulation of NR3C1 via activating protein-1 (AP-1)-mediated transrepression. Collectively, our study elucidates the role of NG2 in GC resistance in MLLr B-ALL through FLT3/AP-1-mediated downregulation of NR3C1, providing novel therapeutic avenues for MLLr B-ALL.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"2002-2017"},"PeriodicalIF":21.0,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141878347","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":"Epigenetic regulation of noncanonical menin targets modulates menin inhibitor response in acute myeloid leukemia.","authors":"Xinyue Zhou, Lixia Zhang, Sajesan Aryal, Virginia Veasey, Amanda Tajik, Cecilia Restelli, Steven Moreira, Pengcheng Zhang, Yanfeng Zhang, Kristin J Hope, Yang Zhou, Changde Cheng, Ravi Bhatia, Rui Lu","doi":"10.1182/blood.2023023644","DOIUrl":"10.1182/blood.2023023644","url":null,"abstract":"<p><strong>Abstract: </strong>Menin inhibitors that disrupt the menin-MLL interaction hold promise for treating specific acute myeloid leukemia (AML) subtypes, including those with KMT2A rearrangements (KMT2A-r), yet resistance remains a challenge. Here, through systematic chromatin-focused CRISPR screens, along with genetic, epigenetic, and pharmacologic studies in a variety of human and mouse KMT2A-r AML models, we uncovered a potential resistance mechanism independent of canonical menin-MLL targets. We show that a group of noncanonical menin targets, which are bivalently cooccupied by active menin and repressive H2AK119ub marks, are typically downregulated after menin inhibition. Loss of polycomb repressive complex 1.1 (PRC1.1) subunits, such as polycomb group ring finger 1 (PCGF1) or BCL6 corepressor (BCOR), leads to menin inhibitor resistance by epigenetic reactivation of these noncanonical targets, including MYC. Genetic and pharmacological inhibition of MYC can resensitize PRC1.1-deficient leukemia cells to menin inhibition. Moreover, we demonstrate that leukemia cells with the loss of PRC1.1 subunits exhibit reduced monocytic gene signatures and are susceptible to BCL2 inhibition, and that combinational treatment with venetoclax overcomes the resistance to menin inhibition in PRC1.1-deficient leukemia cells. These findings highlight the important roles of PRC1.1 and its regulated noncanonical menin targets in modulating the menin inhibitor response and provide potential strategies to treat leukemia with compromised PRC1.1 function.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"2018-2032"},"PeriodicalIF":21.0,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11561541/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141999338","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":"Asciminib monotherapy as frontline treatment of chronic-phase chronic myeloid leukemia: results from the ASCEND study.","authors":"David T Yeung, Naranie Shanmuganathan, John Reynolds, Susan Branford, Mannu Walia, Agnes S M Yong, Jake Shortt, Lynette Chee, Nicholas Viiala, Ilona Cunningham, David M Ross, Alwyn D'Souza, Matthew Wright, Rosemary Harrup, Cecily Forsyth, Robin Filshie, Steven Lane, Peter Browett, Carolyn Grove, Andrew P Grigg, Timothy P Hughes","doi":"10.1182/blood.2024024657","DOIUrl":"10.1182/blood.2024024657","url":null,"abstract":"<p><strong>Abstract: </strong>Asciminib is a myristoyl site BCR::ABL1 inhibitor approved for patients with chronic-phase chronic myeloid leukemia (CP-CML) failing ≥2 prior lines of therapy. The Australasian Leukaemia and Lymphoma Group conducted the Asciminib Evaluation in Newly Diagnosed CML study to assess efficacy of asciminib for newly diagnosed CP-CML. Patients commenced asciminib 40 mg twice daily. Patients with treatment failure, defined as BCR::ABL1 of >10% at 3 or 6 months, or >1% at 12 or 18 months, received either imatinib, nilotinib, or dasatinib in addition to asciminib. In patients with suboptimal response, defined as levels of 1% to 10% at 6 months, >0.1% to 1% at 12 months, or >0.01% to 1% at 18 months, the asciminib dose was increased to 80 mg twice daily. With a median follow-up of 21 months (range, 0-36), 82 of 101 patients continue asciminib. Most common reasons for treatment discontinuation were adverse events (6%), loss of response (4%), and withdrawn consent (5%). There were no deaths; 1 patient developed lymphoid blast crisis. The coprimary end points were early molecular response (BCR::ABL1 of ≤10% at 3 months), achieved in 93% (96% confidence interval [CI], 86-97%), and major molecular response by 12 months achieved in 79%; (95% CI, 70-87%), respectively. Cumulative incidence of molecular response 4.5 was 53% by 24 months. One patient had 2 cerebrovascular events; no other arterial occlusive events were reported. Asciminib as frontline CP-CML therapy leads to high rates of molecular response with excellent tolerance and a low rate of discontinuation for toxicity. This trial was registered at https://www.anzctr.org.au/ as #ACTRN12620000851965.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"1993-2001"},"PeriodicalIF":21.0,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141892823","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":"Perspectives on drug development in chronic myelomonocytic leukemia: changing the paradigm.","authors":"Anthony M Hunter, Mrinal M Patnaik, Raphael Itzykson, Ruben Mesa, Chatchada Karanes, Yanxia Li, R Angelo de Claro, Kelly J Norsworthy, Marc Theoret, Elizabeth Pulte, Eric Padron","doi":"10.1182/blood.2024025648","DOIUrl":"10.1182/blood.2024025648","url":null,"abstract":"<p><strong>Abstract: </strong>Drug development for chronic myelomonocytic leukemia (CMML) has failed to parallel the recent success observed in related myeloid neoplasms. To address these shortcomings, the US Food and Drug Administration (FDA) held a \"Mini-symposium on CMML: Current State of the Art and Trial Design\" in September 2023. This symposium brought together a panel of key FDA regulators and academic experts in CMML drug development to discuss challenges and provide perspectives on future drug development for this disease. The panel explored unique challenges that underlie the lack of therapeutic advances in CMML to date and discussed relevant topics such as clinical trial design, study end points, and key regulatory considerations. This article summarizes the key points of discussion from this symposium to facilitate advancements in the field.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":"144 19","pages":"1987-1992"},"PeriodicalIF":21.0,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142603161","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":"Raab MS, Breitkreutz I, Tonon G, et al. Targeting PKC: a novel role for beta-catenin in ER stress and apoptotic signaling. Blood. 2009;113(7):1513-1521.","authors":"","doi":"10.1182/blood.2024026968","DOIUrl":"https://doi.org/10.1182/blood.2024026968","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"144 19","pages":"2068"},"PeriodicalIF":21.0,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142603166","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":"Risk prediction for clonal cytopenia: multicenter real-world evidence.","authors":"Zhuoer Xie, Rami Komrokji, Najla Al Ali, Alexandra Regelson, Susan Geyer, Anand Patel, Caner Saygin, Amer M Zeidan, Jan Philipp Bewersdorf, Lourdes Mendez, Ashwin Kishtagari, Joshua F Zeidner, Catherine C Coombs, Yazan F Madanat, Stephen Chung, Talha Badar, James Foran, Pinkal Desai, Charlton Tsai, Elizabeth A Griffiths, Monzr M Al Malki, Idoroenyi Amanam, Catherine Lai, H Joachim Deeg, Lionel Ades, Cecilia Arana Yi, Afaf E G Osman, Shira Dinner, Yasmin Abaza, Justin Taylor, Namrata Chandhok, Deborah Soong, Andrew M Brunner, Hetty E Carraway, Abhay Singh, Chiara Elena, Jacqueline Ferrari, Anna Gallì, Sara Pozzi, Eric Padron, Mrinal M Patnaik, Luca Malcovati, Michael R Savona, Aref Al-Kali","doi":"10.1182/blood.2024024756","DOIUrl":"10.1182/blood.2024024756","url":null,"abstract":"<p><strong>Abstract: </strong>Clonal cytopenia of undetermined significance (CCUS) represents a distinct disease entity characterized by myeloid-related somatic mutations with a variant allele fraction of ≥2% in individuals with unexplained cytopenia(s) but without a myeloid neoplasm (MN). Notably, CCUS carries a risk of progressing to MN, particularly in cases featuring high-risk mutations. Understanding CCUS requires dedicated studies to elucidate its risk factors and natural history. Our analysis of 357 patients with CCUS investigated the interplay between clonality, cytopenia, and prognosis. Multivariate analysis identified 3 key adverse prognostic factors: the presence of splicing mutation(s) (score = 2 points), platelet count of <100 × 109/L (score = 2.5), and ≥2 mutations (score = 3). Variable scores were based on the coefficients from the Cox proportional hazards model. This led to the development of the clonal cytopenia risk score (CCRS), which stratified patients into low- (score of <2.5 points), intermediate- (score of 2.5 to <5), and high-risk (score of ≥5) groups. The CCRS effectively predicted 2-year cumulative incidence of MN for low- (6.4%), intermediate- (14.1%), and high-risk (37.2%) groups, respectively, by the Gray test (P < .0001). We further validated the CCRS by applying it to an independent CCUS cohort of 104 patients, demonstrating a c-index of 0.64 (P = .005) in stratifying the cumulative incidence of MN. Our study underscores the importance of integrating clinical and molecular data to assess the risk of CCUS progression, making the CCRS a valuable tool that is practical and easily calculable. These findings are clinically relevant, shaping the management strategies for CCUS and informing future clinical trial designs.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"2033-2044"},"PeriodicalIF":21.0,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11561536/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141598396","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":"B-cell acute lymphoblastic leukemia with MEF2D::BCL9 rearrangement mimicking a Burkitt lymphoma.","authors":"Simon Chevalier, Clémentine Legrand","doi":"10.1182/blood.2024026200","DOIUrl":"https://doi.org/10.1182/blood.2024026200","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"144 19","pages":"2067"},"PeriodicalIF":21.0,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142603142","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":"Genotyped RhD+ red cells for D-positive patients with sickle cell disease with conventional RHD and unexpected anti-D.","authors":"Stella T Chou, Julia Mewha, David F Friedman, Victoria Lazariu, Shaimaa Makrm, Gorka Ochoa, Sunitha Vege, Connie M Westhoff","doi":"10.1182/blood.2024025602","DOIUrl":"10.1182/blood.2024025602","url":null,"abstract":"<p><strong>Abstract: </strong>Anti-D can occur in D-positive patients who inherit RHD genetic variants encoding partial D antigen expression, but unexpected anti-D is also found in the plasma of patients with sickle cell disease who have conventional RHD gene(s) and are transfused with units from Black donors. These anti-D are likely stimulated by variant Rh expressed on donor cells; however, patients with anti-D, regardless of cause, are transfused for a lifetime with D-negative (Rh-negative) blood. This results in significant increased use of Rh-negative units, especially for those requiring chronic transfusion, which can strain Rh-negative blood inventories. We tested whether D-positive patients who made anti-D and had conventional RhD by RHD genotyping could safely be returned to D-positive transfusions without anti-D reappearance or compromised red blood cell survival using RHD genotype-matched units from Black donors. Five patients receiving chronic red cell exchange received an increasing number of D-positive units per procedure with a total of 72 D-positive RHD genotyped units transfused, with no anti-D restimulation. Unexpected anti-C and anti-E were identified during the study associated with donors with variant RHCE alleles. RH genotyping of D-positive units for transfusion may improve use and allocation of valuable Black donor units and reduce demand for Rh-negative blood. This trial was registered at www.clinicaltrials.gov as NCT04156906.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"2045-2049"},"PeriodicalIF":21.0,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11561532/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142035212","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}