HaematologicaPub Date : 2024-10-17DOI: 10.3324/haematol.2024.286061
Ludovica Marando,Clifford M Csizmar,Mrinal M Patnaik
{"title":"Chronic myelomonocytic leukemia: molecular pathogenesis and therapeutic innovations.","authors":"Ludovica Marando,Clifford M Csizmar,Mrinal M Patnaik","doi":"10.3324/haematol.2024.286061","DOIUrl":"https://doi.org/10.3324/haematol.2024.286061","url":null,"abstract":"Chronic myelomonocytic leukemia (CMML) is an aggressive clonal stem cell disorder categorized amongst myelodysplastic/myeloproliferative (MDS/MPN) overlap neoplasms. While sharing features with both MDS and MPN, CMML has distinct molecular and clinical profiles. The presence of CMML-specific prognostic models, response criteria, and dedicated clinical trials underscores a unique and complex biology. Agerelated changes affecting the bone marrow microenvironment, immune responses, and the intricate balance between epigenetic deregulation and proinflammatory signaling are characteristic of this disease, collectively posing significant scientific and clinical challenges in management. CMML is an ageing-related, clinically heterogeneous neoplasm with limited approved therapeutic options, representing an area of unmet medical need. This review offers a comprehensive analysis of the current understanding of the molecular mechanisms driving CMML evolution and its clinical manifestations within the ever-evolving landscape of precision medicine. In light of the most recent molecular discoveries, we highlight the pitfalls of existing therapies and underscore promising investigational agents. Many of the biological findings discussed are shared across a spectrum of acute and chronic myeloid neoplasms, as well as clonal hematopoiesis, broadening the scope of this review.","PeriodicalId":12964,"journal":{"name":"Haematologica","volume":"3 1","pages":""},"PeriodicalIF":10.1,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142448034","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}
HaematologicaPub Date : 2024-10-17DOI: 10.3324/haematol.2024.285752
Bin Hu,Han Gong,Ling Nie,Ji Zhang,Yanan Li,Dandan Liu,Huifang Zhang,Haihang Zhang,Lu Han,Chaoying Yang,Maohua Li,Wenwen Xu,Yukio Nakamura,Lihong Shi,Mao Ye,Christopher D Hillyer,Narla Mohandas,Long Liang,Yue Sheng,Jing Liu
{"title":"Lysine succinylation precisely controls normal erythropoiesis.","authors":"Bin Hu,Han Gong,Ling Nie,Ji Zhang,Yanan Li,Dandan Liu,Huifang Zhang,Haihang Zhang,Lu Han,Chaoying Yang,Maohua Li,Wenwen Xu,Yukio Nakamura,Lihong Shi,Mao Ye,Christopher D Hillyer,Narla Mohandas,Long Liang,Yue Sheng,Jing Liu","doi":"10.3324/haematol.2024.285752","DOIUrl":"https://doi.org/10.3324/haematol.2024.285752","url":null,"abstract":"Lysine succinylation (Ksu) has recently emerged as a protein modification that regulates diverse functions in various biological processes. However, the systemically and precise role of lysine succinylation in erythropoiesis remains to be fully elucidated. In this study, we noted a prominent increase of succinyl-CoA and lysine succinylation during human erythroid differentiation. To explore the functional significance of succinylation, we inhibited succinylation by either knock downing key succinyltransferases or overexpressing desuccinylases. Succinylation inhibition led to suppressed cell proliferation, increased apoptosis, and disrupted erythroid differentiation. In vivo overexpression of the desuccinylases SIRT5 delayed erythroid differentiation. Furthermore, integrative proteome and succinylome analysis identifies 939 succinylated proteins with 3,562 Ksu sites, distributed across various cellular compartments and involved in multiple cellular processes. Significantly, inconsistencies between protein expression levels and succinylation levels were observed, indicating that the succinylation of certain proteins may function independently of expression. Mechanistically, we implicated KAT2A-mediated succinylation of histone H3 K79, leading to chromatin remodeling and subsequently erythropoiesis regulation. Specially, we identified CYCS as a key regulator of erythropoiesis, which depends on its succinylation sites K28/K40. Taken together, our comprehensive investigation of the succinylation landscape during erythropoiesis provides valuable insights into its regulatory role and offer potential implications for erythroid-related diseases.","PeriodicalId":12964,"journal":{"name":"Haematologica","volume":"44 1","pages":""},"PeriodicalIF":10.1,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142448039","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}
HaematologicaPub Date : 2024-10-17DOI: 10.3324/haematol.2024.286369
J Scott Beeler,Rahul Peravali,Kristan M Augustin,Amy C M Musiek,Kiran Vij,Dilan A Patel,John F DiPersio
{"title":"Severe acute cutaneous only graft-versus-host disease after late relapse of chronic myeloid leukemia and ultraviolet B phototherapy.","authors":"J Scott Beeler,Rahul Peravali,Kristan M Augustin,Amy C M Musiek,Kiran Vij,Dilan A Patel,John F DiPersio","doi":"10.3324/haematol.2024.286369","DOIUrl":"https://doi.org/10.3324/haematol.2024.286369","url":null,"abstract":"Not available.","PeriodicalId":12964,"journal":{"name":"Haematologica","volume":"232 1","pages":""},"PeriodicalIF":10.1,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142448047","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":"Different inflammatory, fibrotic, and immunologic signatures between pre-fibrotic and overt primary myelofibrosis.","authors":"Seung-Hyun Jung, Sung-Eun Lee, Sujin Yun, Da-Eun Min, Youngjin Shin, Yeun-Jun Chung, Sug Hyung Lee","doi":"10.3324/haematol.2024.285598","DOIUrl":"https://doi.org/10.3324/haematol.2024.285598","url":null,"abstract":"<p><p>Primary myelofibrosis (PMF) is a myeloid proliferative neoplasm (MPN) characterized by bone marrow (BM) fibrosis. Pre-fibrotic PMF (pre-PMF) progresses to overt PMF. Megakaryocytes (MKs) play a primary role in PMF; however, the functions of MK subsets and those of other hematopoietic cells during PMF progression remain unclarified. Therefore, we analyzed BM aspirates in pre-PMFs, overt PMFs, and other MPNs using single-cell RNA sequencing (scRNA-seq). We identified 14 cell types with subsets, including hematopoietic stem and progenitor cells (HSPCs) and MKs. HSPCs in overt PMF were MK-biased and inflammation/fibrosis-enriched. Among MKs, the epithelial-mesenchymal transition (EMT)-enriched subset was abruptly increased in overt PMF. MKs in non-fibrotic/non-PMF MPN were MK differentiation-enriched, whereas those in fibrotic/non-PMF MPN were inflammation/fibrosis-enriched. Overall, the inflammation/fibrosis signatures of the HSPC, MK, and CD14+ monocyte subsets increased from pre-PMF to overt PMF. Cytotoxic and dysfunctional scores also increased in T and NK cells. Clinically, MK and HSPC subsets with high inflammation/fibrosis signatures were frequent in the patients with peripheral blood blasts ≥1%. scRNA-seq predicted higher cellular communications of MK differentiation, inflammation/fibrosis, immunologic effector/dysfunction, and tumor-associated signaling in overt PMF than pre-PMF. However, no decisive subset emerged during PMF progression. Our study demonstrated that HSPCs, monocytes, and lymphoid cells contribute to PMF progression, and subset specificity existed regarding inflammation/fibrosis and immunologic dysfunction. PMF progression may depend on multiple cell types' alterations, and EMTenriched MKs may be potential targets for the diagnosis and therapy of the progression.</p>","PeriodicalId":12964,"journal":{"name":"Haematologica","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142390070","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}
HaematologicaPub Date : 2024-10-10DOI: 10.3324/haematol.2024.286168
Suheil Albert Atallah-Yunes, Matthew J Rees, Thomas E Witzig, Thomas M Habermann, Javier Munoz, Madiha Iqbal, Ellen D McPhail, Grzegorz S Nowakowski
{"title":"CODOX-M/IVAC-R <i>versus</i> DA-EPOCH-R in double hit/triple hit lymphoma patients aged 60 years or under.","authors":"Suheil Albert Atallah-Yunes, Matthew J Rees, Thomas E Witzig, Thomas M Habermann, Javier Munoz, Madiha Iqbal, Ellen D McPhail, Grzegorz S Nowakowski","doi":"10.3324/haematol.2024.286168","DOIUrl":"https://doi.org/10.3324/haematol.2024.286168","url":null,"abstract":"<p><p>Intensified chemoimmunotherapy regimens are often used in young patients with double hit and triple hit lymphoma (DHL/THL) despite no survival benefit compared to R-CHOP. Favorable retrospective reports on the application of CODOX-M/IVAC-R are subject to selection bias as only young fit patients can tolerate this treatment. We conducted a retrospective analysis to investigate outcome differences between CODOX-M/IVAC-R and DA-EPOCH-R in DHL/THL patients aged 60 years or younger. 113 patients were identified; CODOX-M/IVAC-R (N=49) and DA-EPOCH-R (N=64). 80% (39/49) achieved complete (CR) after completing CODOX-M/IVAC-R compared to 58% (37/64) with DA-EPOCH-R. The median follow-up was 5.3 years and 3.3 years for the CODOX-M/IVAC-R and DA-EPOCH-R group respectively. CODOX-M/IVAC-R demonstrated superior EFS on univariate (HR=0.54, 95%CI=0.31-0.97) and multivariable analysis adjusted for age, BCL translocation (BCL2 vs BCL6 vs both), IPI score and receipt of ASCT (aHR=0.52, 95%CI=0.29-0.93); however there was no significant influence on OS (aHR=0.92, 95%CI=0.46-1.84). The 1, 2 and 5 years EFS in the CODOX-M/IVAC-R group was 68.3%, 64.1% and 61.5% respectively compared to 52.4%, 48.9% and 39.5% respectively in the DA-EPOCH-R group. Primary refractory disease or relapse occurred in 33% (16/49) of CODOX-M/IVAC-R and 54% (35/64) of DA-EPOCH-R recipients, and produced median OS of 10.3 months and 33.7 months, respectively, indicating poor outcomes in the CODOX-M/IVAC-R subgroup with R/R disease. More patients were able to receive subsequent salvage therapies in the DA-EPOCH-R group. No patients died of regimen toxicity and the rates of CNS relapse and therapy related hematologic neoplasms were similar in both groups.</p>","PeriodicalId":12964,"journal":{"name":"Haematologica","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142390068","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}
HaematologicaPub Date : 2024-10-10DOI: 10.3324/haematol.2024.285701
Jana Trifinopoulos, Julia List, Thorsten Klampfl, Klara Klein, Michaela Prchal-Murphy, Agnieszka Witalisz-Siepracka, Florian Bellutti, Luca L Fava, Gerwin Heller, Sarah Stummer, Patricia Testori, Monique L Den Boer, Judith M Boer, Sonja Marinovic, Gregor Hoermann, Wencke Walter, Andreas Villunger, Piotr Sicinski, Veronika Sexl, Dagmar Gotthardt
{"title":"Cyclin C promotes development and progression of B-cell acute lymphoblastic leukemia by counteracting p53-mediated stress responses.","authors":"Jana Trifinopoulos, Julia List, Thorsten Klampfl, Klara Klein, Michaela Prchal-Murphy, Agnieszka Witalisz-Siepracka, Florian Bellutti, Luca L Fava, Gerwin Heller, Sarah Stummer, Patricia Testori, Monique L Den Boer, Judith M Boer, Sonja Marinovic, Gregor Hoermann, Wencke Walter, Andreas Villunger, Piotr Sicinski, Veronika Sexl, Dagmar Gotthardt","doi":"10.3324/haematol.2024.285701","DOIUrl":"https://doi.org/10.3324/haematol.2024.285701","url":null,"abstract":"<p><p>Despite major therapeutic advances in the treatment of acute lymphoblastic leukemia (ALL), resistances and long-term toxicities still pose significant challenges. Cyclins and their associated cyclin-dependent kinases are one focus of cancer research when looking for targeted therapies. We discovered cyclin C as a key factor for B-ALL development and maintenance. While cyclin C is non-essential for normal hematopoiesis, CcncΔ/Δ BCR::ABL1+ B-ALL cells fail to elicit leukemia in mice. RNA sequencing experiments revealed a p53 pathway deregulation in CcncΔ/Δ BCR::ABL1+ cells resulting in the incapability of the leukemic cells to adequately respond to stress. A genome-wide CRISPR/Cas9 loss-of-function screen supplemented with additional knock-outs unveiled a dependency of human B-lymphoid cell lines on CCNC. High cyclin C levels in B-cell precursor (BCP) ALL patients were associated with poor event-free survival and increased risk of early disease recurrence after remission. Our findings highlight cyclin C as potential therapeutic target for B-ALL, particularly to enhance cancer cell sensitivity to stress and chemotherapy.</p>","PeriodicalId":12964,"journal":{"name":"Haematologica","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142390069","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}
HaematologicaPub Date : 2024-10-10DOI: 10.3324/haematol.2024.285448
Federico Mosna, Erika Borlenghi, Mark Litzow, John C Byrd, Cristina Papayannidis, Cristina Tecchio, Felicetto Ferrara, Guido Marcucci, Roberto Cairoli, Elizabeth A Morgan, Carmela Gurrieri, Cecilia C S Yeung, H Joachim Deeg, Debora Capelli, Anna Candoni, Jason R Gotlib, Monia Lunghi, Sheeja Pullarkat, Francesco Lanza, Sara Galimberti, Fabio Forghieri, Adriano Venditti, Moreno Festuccia, Ernesta Audisio, Denise Marvalle, Gian Matteo Rigolin, Giovanni Roti, Eros DiBona, Giuseppe Visani, Francesco Albano, Ann-Kathrin Eisfeld, Peter Valent, Gerwin Huls, Gautam Borthakur, Mauro Krampera, Giovanni Martinelli, Nicolaus Kröger, Alessandra Sperotto, Michele Gottardi
{"title":"Long-term survival can be achieved in a significant fraction of older patients with core binding factor acute myeloid leukemia treated with intensive chemotherapy.","authors":"Federico Mosna, Erika Borlenghi, Mark Litzow, John C Byrd, Cristina Papayannidis, Cristina Tecchio, Felicetto Ferrara, Guido Marcucci, Roberto Cairoli, Elizabeth A Morgan, Carmela Gurrieri, Cecilia C S Yeung, H Joachim Deeg, Debora Capelli, Anna Candoni, Jason R Gotlib, Monia Lunghi, Sheeja Pullarkat, Francesco Lanza, Sara Galimberti, Fabio Forghieri, Adriano Venditti, Moreno Festuccia, Ernesta Audisio, Denise Marvalle, Gian Matteo Rigolin, Giovanni Roti, Eros DiBona, Giuseppe Visani, Francesco Albano, Ann-Kathrin Eisfeld, Peter Valent, Gerwin Huls, Gautam Borthakur, Mauro Krampera, Giovanni Martinelli, Nicolaus Kröger, Alessandra Sperotto, Michele Gottardi","doi":"10.3324/haematol.2024.285448","DOIUrl":"https://doi.org/10.3324/haematol.2024.285448","url":null,"abstract":"<p><p>Acute Myeloid Leukemia is mainly a disease of the elderly: however, the knowledge on the outcomes of treatment in core binding factor AML (CBFAML) in older population, is limited. We retrospectively collected data on 229 patients with CBF- AML followed long-term in the last two decades. A 5-year overall survival (OS) of 44.2% (95%CI, 39.9-47.5) and a 5-year event - free survival (EFS) of 32.9% (95%CI, 25.5-40.1) was observed. In a subgroup of >70-year patients who completed intensive therapy (induction + >3 courses of consolidation including autologous stem cell transplant: 10 patients) the median EFS was 11.8 months (95%CI, 9.4 - 15.2) and OS was 40.0% (95%CI, 36.4 - 44.1) at 5yr. In univariate analysis, age >70 (hazard ratio (HR) 1.78, [95%CI, 1.15 - 2.54], p=.008), failure to achieve remission following induction (HR, 8.96 [95%CI, 5.5 - 13.8], p=<.0001), no consolidation therapy (HR, 0.75 [95%CI, 0.47 - 1.84], p=.04) and less than 3 cycles of consolidation (HR, 1.48 [95%CI, 0.75 - 3.2], p=.0004), predicted poorer EFS. Our study shows that intensive therapy, in selected older CBF-AML patients, leads to longer survival. Achieving a CR seems to be the most important first step and at least 3 cycles of consolidation, an important second one. The analysis suggests that these patients should not be excluded from studies with intensive therapies.</p>","PeriodicalId":12964,"journal":{"name":"Haematologica","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142390073","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}
HaematologicaPub Date : 2024-10-10DOI: 10.3324/haematol.2024.286340
Valentin Clichet, Thomas Boyer
{"title":"Artificial intelligence-based Myelodysplastic Syndromes Score, 2022 classifications, and the Molecular International Prognostic Scoring System : a perfect match.","authors":"Valentin Clichet, Thomas Boyer","doi":"10.3324/haematol.2024.286340","DOIUrl":"https://doi.org/10.3324/haematol.2024.286340","url":null,"abstract":"<p><p>Not available.</p>","PeriodicalId":12964,"journal":{"name":"Haematologica","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142390066","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}
HaematologicaPub Date : 2024-10-10DOI: 10.3324/haematol.2024.286157
Florentien E M In 't Hout, Thessa N Scheele, Theresia M Westers, Canan Alhan, Carolien Duetz, Eline M P Cremers, Heleen A Visser-Wisselaar, Annelies Verbrugge, Dana A Chitu, Bert A Van der Reijden, Aniek O De Graaf, Arjan A Van de Loosdrecht, Joop H Jansen
{"title":"Expression levels of genes implicated in the working mechanism of lenalidomide predict treatment response in lower risk myelodysplastic syndrome patients.","authors":"Florentien E M In 't Hout, Thessa N Scheele, Theresia M Westers, Canan Alhan, Carolien Duetz, Eline M P Cremers, Heleen A Visser-Wisselaar, Annelies Verbrugge, Dana A Chitu, Bert A Van der Reijden, Aniek O De Graaf, Arjan A Van de Loosdrecht, Joop H Jansen","doi":"10.3324/haematol.2024.286157","DOIUrl":"https://doi.org/10.3324/haematol.2024.286157","url":null,"abstract":"<p><p>Not available.</p>","PeriodicalId":12964,"journal":{"name":"Haematologica","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142390071","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}