Haematologica最新文献_第7页

Bleximenib, the novel menin-KMT2A inhibitor JNJ-75276617, impairs long-term proliferation and immune evasion in acute myeloid leukemia.

IF 8.2 1区医学

Haematologica Pub Date : 2024-12-19 DOI: 10.3324/haematol.2024.285616

Shanna M Hogeling, Duy Minh Lê, Nikita La Rose, Min Chul Kwon, Albertus T J Wierenga, Fiona A J Van den Heuvel, Vincent Van den Boom, Anna Kuchnio, Ulrike Philippar, Gerwin Huls, Jan Jacob Schuringa

{"title":"Bleximenib, the novel menin-KMT2A inhibitor JNJ-75276617, impairs long-term proliferation and immune evasion in acute myeloid leukemia.","authors":"Shanna M Hogeling, Duy Minh Lê, Nikita La Rose, Min Chul Kwon, Albertus T J Wierenga, Fiona A J Van den Heuvel, Vincent Van den Boom, Anna Kuchnio, Ulrike Philippar, Gerwin Huls, Jan Jacob Schuringa","doi":"10.3324/haematol.2024.285616","DOIUrl":"https://doi.org/10.3324/haematol.2024.285616","url":null,"abstract":"Acute myeloid leukemia (AML) remains challenging to treat, which in part relates to genetic heterogeneity of the disease, to the protective tumor microenvironment driving resistance to therapy, and also to immune evasion characteristics of leukemic cells. Targeting epigenetic programs in AML provides an attractive opportunity to impair long-term proliferation and induce differentiation. The novel inhibitor JNJ- 75276617 (bleximenib) targets the menin-KMT2A interaction and provides preclinical efficacy in AML (Kwon et al1). Here, we provide mechanistic insight in how JNJ- 75276617 impairs proliferation and drives differentiation of primary AML patient cells. A large-scale drug screen was set up in which genetic alterations and quantitative proteomics were compared with drug sensitivity in a preclinical setting, which revealed that granulocyte macrophage progenitor (GMP)-like AMLs display the greatest sensitivity. Furthermore, we identified that NPM1c/DNMT3Amut AMLs are sensitive, and some NPM1wt AML subtypes without KMT2A-MLLT3 rearrangements benefit from menin-KMT2A inhibition. Genome-wide ChIP-seq studies revealed patient-specific epigenetic alterations upon JNJ-75276617 treatment, uncovering a striking upregulation of MHC class I and class II expression as a consequence of epigenetic changes upon menin-KMT2A inhibition, independent of MEIS1 loss but involving CIITA activation. Functionally, this results in enhanced sensitivity of leukemic blasts to T cell-mediated cytotoxicity in allogeneic and autologous settings. Our data indicate that JNJ-75276617 provides a potential therapeutic approach whereby not only proliferation is impaired and differentiation is induced, but whereby therapeutic benefit might also be achieved by reactivating the antigen presentation machinery.","PeriodicalId":12964,"journal":{"name":"Haematologica","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142864093","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}

引用次数: 0

Clinical and laboratory risk factors for sickle cell retinopathy and maculopathy: a scoping review of the current evidence.

IF 8.2 1区医学

Haematologica Pub Date : 2024-12-19 DOI: 10.3324/haematol.2024.286420

Rajani P Brandsen, Roselie M H Diederen, Gizem Kocabas, Erfan Nur, Arjan Malekzadeh, Reinier O Schlingemann, Bart J Biemond

引用次数: 0

Binding of therapeutic Fc-fused factor VIII to the neonatal Fc receptor at neutral pH associates with poor half-life extension.

IF 8.2 1区医学

Haematologica Pub Date : 2024-12-12 DOI: 10.3324/haematol.2024.286536

Alejandra Reyes-Ruiz, Sandrine Delignat, Aishwarya Sudam Bhale, Victoria Daventure, Robin V Lacombe, Leslie Dourthe, Olivier Christophe, Sune Justesen, Krishnan Venkataraman, Jordan D Dimitrov, Sebastien Lacroix-Desmazes

{"title":"Binding of therapeutic Fc-fused factor VIII to the neonatal Fc receptor at neutral pH associates with poor half-life extension.","authors":"Alejandra Reyes-Ruiz, Sandrine Delignat, Aishwarya Sudam Bhale, Victoria Daventure, Robin V Lacombe, Leslie Dourthe, Olivier Christophe, Sune Justesen, Krishnan Venkataraman, Jordan D Dimitrov, Sebastien Lacroix-Desmazes","doi":"10.3324/haematol.2024.286536","DOIUrl":"https://doi.org/10.3324/haematol.2024.286536","url":null,"abstract":"Fusion of therapeutic proteins to the Fc fragment of human IgG1 promotes their FcRn-mediated recycling and subsequent extension in circulating half-life. However, different Fc-fused proteins, as well as antibodies with different variable domains but identical Fc, may differ in terms of extension in half-life. Here we compared the binding behaviour to FcRn of Fc-fused FVIII, Fc-fused FIX and two human monoclonal HIV-1 broadly-neutralizing IgG1, m66.6 and VRC01 with identical Fc. While all molecules bound FcRn at acidic pH, only rFVIIIFc and m66.6 interacted with FcRn at neutral pH. In silico modelling predicted a role for charged residues in the C1 and C2 domains of FVIII, and in the variable domains of m66.6, in the neutral binding to FcRn. Accordingly, mutations of key positively charged amino-acids in the FVIII C1C2 domains decreased the binding of the protein to FcRn at pH 7.4 in vitro and increased the half-life of rFVIIIFc in VWFKO mice. Our findings suggest that the removal of positively charged patches on Fc-fused proteins to ameliorate FcRn recycling without affecting therapeutic efficacy, may improve their pharmacokinetic properties.","PeriodicalId":12964,"journal":{"name":"Haematologica","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142812934","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}

引用次数: 0

Clinical interrogation of TP53 aberrations and its impact on survival in patients with myeloid neoplasms.

IF 8.2 1区医学

Haematologica Pub Date : 2024-12-12 DOI: 10.3324/haematol.2024.286465

Jayastu Senapati, Sanam Loghavi, Guillermo Garcia-Manero, Guillin Tang, Tapan Kadia, Nicholas J Short, Hussein A Abbas, Naszrin Arani, Courtney D DiNardo, Gautam Borthakur, Naveen Pemmaraju, Betul Oran, Elizabeth Shpall, Uday Popat, Richard Champlin, Sherry Pierce, Sankalp Arora, Ghayas Issa, Musa Yilmaz, Keyur Patel, Koichi Takahashi, Guillermo Montalban-Bravo, Danielle Hammond, Fadi G Haddad, Farhad Ravandi, Hagop M Kantarjian, Naval G Daver

{"title":"Clinical interrogation of TP53 aberrations and its impact on survival in patients with myeloid neoplasms.","authors":"Jayastu Senapati, Sanam Loghavi, Guillermo Garcia-Manero, Guillin Tang, Tapan Kadia, Nicholas J Short, Hussein A Abbas, Naszrin Arani, Courtney D DiNardo, Gautam Borthakur, Naveen Pemmaraju, Betul Oran, Elizabeth Shpall, Uday Popat, Richard Champlin, Sherry Pierce, Sankalp Arora, Ghayas Issa, Musa Yilmaz, Keyur Patel, Koichi Takahashi, Guillermo Montalban-Bravo, Danielle Hammond, Fadi G Haddad, Farhad Ravandi, Hagop M Kantarjian, Naval G Daver","doi":"10.3324/haematol.2024.286465","DOIUrl":"https://doi.org/10.3324/haematol.2024.286465","url":null,"abstract":"In myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) with TP53 aberrations, dissecting the interaction amongst patient, disease and treatment factors are important for therapeutic decisions and prognostication. This retrospective analysis included patients with newly diagnosed MDS (>5% blasts) and AML with TP53 mutation(s) treated at MD Anderson Cancer Center. We factored patient age, TP53 aberration burden, therapy intensity and use of venetoclax in the AML subgroup, and allogeneic hematopoietic stem cell transplantation (HSCT) to interrogate outcomes. TP53 was annotated as high-risk (TP53HR) if >1 mutation, one mutation + allelic deletion or a single mutation with variant allele frequency (VAF) ≥40%; TP53 low risk (TP53LR) included a single TP53 mutation VAF.","PeriodicalId":12964,"journal":{"name":"Haematologica","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142812942","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}

引用次数: 0

Acquired thrombotic thrombocytopenic purpura of unidentified pathophysiology in patients with severe disease: completing the landscape of thrombotic thrombocytopenic purpura.

IF 8.2 1区医学

Haematologica Pub Date : 2024-12-12 DOI: 10.3324/haematol.2024.286932

Bérangère S Joly, Mathilde Leclercq, Ygal Benhamou, Agnès Veyradier, Paul Coppo

引用次数: 0

Characterization of tumor microenvironment and cell interaction patterns in testicular and diffuse large B-cell lymphomas.

IF 8.2 1区医学

Haematologica Pub Date : 2024-12-12 DOI: 10.3324/haematol.2024.286267

Matias Autio, Oscar Brück, Marjukka Pollari, Marja-Liisa Karjalainen-Lindsberg, Klaus Beiske, Judit Mészaros Jørgensen, Harald Holte, Teijo Pellinen, Suvi-Katri Leivonen, Sirpa Leppä

{"title":"Characterization of tumor microenvironment and cell interaction patterns in testicular and diffuse large B-cell lymphomas.","authors":"Matias Autio, Oscar Brück, Marjukka Pollari, Marja-Liisa Karjalainen-Lindsberg, Klaus Beiske, Judit Mészaros Jørgensen, Harald Holte, Teijo Pellinen, Suvi-Katri Leivonen, Sirpa Leppä","doi":"10.3324/haematol.2024.286267","DOIUrl":"https://doi.org/10.3324/haematol.2024.286267","url":null,"abstract":"The tumor microenvironments (TME) of diffuse large B-cell lymphoma (DLBCL) subgroups have remained poorly characterized. Here, we dissected the composition and spatial organization of the TME in germinal center B-cell (GCB), activated B-cell (ABC), and testicular DLBCLs (T-DLBCL) using gene expression profiling and multiplex immunohistochemistry. We found that high proportions of M2-like tumor-associated macrophages (TAMs) and cytotoxic tumor-infiltrating T cells (TILs) were characteristic of ABC DLBCL TME. Furthermore, high CD8+ TIL content translated to favorable outcomes. In contrast, GCB DLBCL TME was enriched in CD4+ TILs, regulatory TILs, and a higher M1-like/M2-like TAM ratio, and high proportions of TAMs and Granzyme B+ cells associated with worse survival. TILs and TAMs interacted more frequently with M2-like TAMs and cytotoxic TILs in the ABC DLBCLs contrary to GCB subtype, where the interactions were more abundant with other TILs and CD4+ TILs. In T-DLBCL, TME resembled that of ABC DLBCL with a higher proportion of M2-like TAMs and cytotoxic cells, except that checkpoint-positive TILs were less prominent compared to DLBCL NOS. Cytotoxic TILs also interacted more with TILs and TAMs. A high amount of CD163+ TAM interactions with distinct TILs translated to unfavorable survival both in GCB DLBCL and T-DLBCL, whereas a high number of interactions between TILs and TAMs, CD4+ TILs and TAMs, and CD4+ TILs and other TILs associated with favorable outcomes only in T-DLBCL. Together, our data demonstrate biologically and clinically relevant differences in the composition of and cellular interactions in the TME between various DLBCL entities.","PeriodicalId":12964,"journal":{"name":"Haematologica","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142812938","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}

引用次数: 0

Five-year outcomes of CD19 followed by CD22 chimeric antigen receptor T-cell therapy in B-cell acute lymphoblastic leukemia patients who relapsed after allo-transplantation.

IF 8.2 1区医学

Haematologica Pub Date : 2024-12-12 DOI: 10.3324/haematol.2024.286534

Shuangyou Liu, Lihong An, Zhichao Yin, Yuehui Lin, Zhuojun Ling, Biping Deng, Xinjian Yu, Qinlong Zheng, Defeng Zhao, Tong Wu, Alex H Chang, Chunrong Tong

引用次数: 0

FVIII peptides presented on HLA-DP and identification of an A3 domain peptide binding with high affinity to the commonly expressed HLA-DP4.

IF 8.2 1区医学

Haematologica Pub Date : 2024-12-12 DOI: 10.3324/haematol.2024.286204

Mariarosaria Miranda, Bjarke Endel Hansen, Batoul Wehbi, Valeria Porcheddu, Floris P J Van Alphen, Paul Kaijen, Karin Fijnvandraat, Sebastien Lacroix-Desmazes, Maartje Van den Biggelaar, Bernard Maillere, Jan Voorberg

{"title":"FVIII peptides presented on HLA-DP and identification of an A3 domain peptide binding with high affinity to the commonly expressed HLA-DP4.","authors":"Mariarosaria Miranda, Bjarke Endel Hansen, Batoul Wehbi, Valeria Porcheddu, Floris P J Van Alphen, Paul Kaijen, Karin Fijnvandraat, Sebastien Lacroix-Desmazes, Maartje Van den Biggelaar, Bernard Maillere, Jan Voorberg","doi":"10.3324/haematol.2024.286204","DOIUrl":"https://doi.org/10.3324/haematol.2024.286204","url":null,"abstract":"The development of neutralizing antibodies (inhibitors) against coagulation factor VIII (FVIII) poses a major challenge in hemophilia A (HA) treatment. The formation of FVIII inhibitors is a CD4+ T-cell dependent mechanism which includes antigen presenting cells (APCs), B- and T-helper lymphocytes. APCs present FVIII derived peptides on major histocompatibility complex class II (MHC-II) to CD4+ Tcells. We previously established a mass spectrometry based approach to delineate the FVIII repertoire presented on HLA-DR and HLA-DQ. In this study, specific attention was directed towards the identification of FVIII peptides presented on HLA-DP. A data-set of naturally processed FVIII peptides was generated by incubating human FVIII with immature monocytes-derived dendritic cells (moDCs) from HLA-typed healthy donors. Using this method, we identified 176 to 1352 different HLA-DP presented peptides per donor, including 26 different FVIII derived peptides. The most frequently presented peptides derived from the A3, and C2 domains of FVIII. Comparison of the FVIII repertoire presented on HLA-DP with that presented on HLA-DR revealed considerable overlap but also suggested preferential presentation of specific peptides on either HLA-DR or HLA-DP. Fourteen FVIII peptides presented on HLA-DP were synthesized and evaluated for their binding ability to the commonly expressed HLA-DP4 molecule which is highly prevalent in the Caucasian population. Peptide binding studies showed that 7 of 14 peptides competed with a reference peptide to HLADP4. Interestingly, an A3 domain derived peptide bound with high affinity to HLA-DP4 positioning this peptide as a prime candidate for the development of novel peptide-based tolerogenic strategies for FVIII inhibitors.","PeriodicalId":12964,"journal":{"name":"Haematologica","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142812946","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}

引用次数: 0

hu128.1, a humanized antibody targeting transferrin receptor 1, blocks erythroleukemia growth in xenograft mouse models.

IF 8.2 1区医学

Haematologica Pub Date : 2024-12-12 DOI: 10.3324/haematol.2024.286518

Tracy R Daniels-Wells, Pierre V Candelaria, Aileen M Rodriguez, Marie-Alix Poul, Manuel L Penichet

引用次数: 0

Cancer-related thrombosis: impact of biological sex on the risk of rethrombosis and bleeding.

IF 8.2 1区医学

Haematologica Pub Date : 2024-12-12 DOI: 10.3324/haematol.2024.286152

Silvia García Adrián, Claudia Iglesias Pérez, Alberto Carmona-Bayonas, Laura Ortega Morán, Jaime Rubio Pérez, Purificación Martínez Del Prado, Eva Martínez De Castro, Fernando Neria, Isaura Fernández Pérez, Marta García De Herreros, Marta Carmona Campos, Ignacio García Escobar, Rut Porta Balanyà, David Marrupe González, Paula Jiménez Fonseca, María Esperanza Guirao García, Manuel Sánchez Cánovas, José Muñoz Langa, Pedro Pérez Segura, Ma José Méndez Vidal, Andrés J Muñoz Martín

{"title":"Cancer-related thrombosis: impact of biological sex on the risk of rethrombosis and bleeding.","authors":"Silvia García Adrián, Claudia Iglesias Pérez, Alberto Carmona-Bayonas, Laura Ortega Morán, Jaime Rubio Pérez, Purificación Martínez Del Prado, Eva Martínez De Castro, Fernando Neria, Isaura Fernández Pérez, Marta García De Herreros, Marta Carmona Campos, Ignacio García Escobar, Rut Porta Balanyà, David Marrupe González, Paula Jiménez Fonseca, María Esperanza Guirao García, Manuel Sánchez Cánovas, José Muñoz Langa, Pedro Pérez Segura, Ma José Méndez Vidal, Andrés J Muñoz Martín","doi":"10.3324/haematol.2024.286152","DOIUrl":"https://doi.org/10.3324/haematol.2024.286152","url":null,"abstract":"Patients with cancer present a higher risk of rethrombosis and bleeding secondary to anticoagulant treatment than individuals without cancer. Given the lack of specific clinical trials, the decision regarding the optimal duration of treatment must consider multiple factors, including sex. The current study used data from the international, prospective TESEO Registry that includes consecutive patients diagnosed with cancer-associated thrombosis (CAT). Between July 2018 and December 2022, 2,823 patients were included in the TESEO Registry, 1,351 (48%) of whom were female. The most common venous thromboembolic event (VTE) in both sexes was pulmonary embolism (PE), with an incidence of 58.0% among men and 54.3% in women (p=0.045). After a median follow-up of 6.9 months (IQR, 1.9-14.4), the rethrombosis rate at the end of follow up was 10.0% in males and 15.0% in females (p=0.14). The location of the primary tumor in the gastrointestinal tract was associated with a greater risk of rethrombosis, whereas sex had no significant impact. Men presented twice as many major bleeds. Additional risk factors for major bleeding included situations of risk due to tumor site or thrombocytopenia, as well as the presence of active tumor bleeding at the time of VTE diagnosis. Overall survival was higher among women. Given the higher incidence of major bleeding among men, sex should be deemed a relevant factor when deciding on the duration of anticoagulant treatment in cancer patients.","PeriodicalId":12964,"journal":{"name":"Haematologica","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142812935","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}

引用次数: 0