HemaSphere最新文献

{"title":"Therapeutic success and epidemiological failure in hematology","authors":"Pierre Sujobert","doi":"10.1002/hem3.70447","DOIUrl":"https://doi.org/10.1002/hem3.70447","url":null,"abstract":"<p>What is the goal of onco-hematology? While perspectives may differ, improving cure rates for patients with hematological malignancies (HMs) is widely considered as the primary objective. Encouragingly, substantial progress has been made toward this goal, as reflected by the marked improvement in 5-year overall survival (OS) for patients with HMs over the past three decades according to the Surveillance, Epidemiology, and End Results (SEER) database<span><sup>1</sup></span> (Figure 1A). Between 1992 and 2017, major gains in 5-year OS were observed in chronic myeloid leukemia (CML, 31%–69%, +38%), multiple myeloma (MM, 27%–64%, +37%), and non-Hodgkin lymphomas (NHLs, 51%–78%, +27%). These improvements are consistent with already published data,<span><sup>2-4</sup></span> and largely attributable to therapeutic innovations, including targeted therapies (e.g., imatinib, bortezomib, and thalidomide derivatives) and monoclonal antibodies (such as rituximab). Significant advances have also been achieved in acute leukemias, including acute lymphoblastic leukemia (ALL, 58%–76%, +18%) and acute myeloid leukemia (AML, 18%–34%, +16%). Improvements have likewise been observed in diseases that already had relatively high 5-year OS rates in 1992, such as chronic lymphocytic leukemia (CLL, 77%–92%, +15%) and Hodgkin lymphoma (HL, 85%–93%, +8%). The continued integration of highly effective treatments such as CAR T-cell therapies, bispecific antibodies, and novel targeted agents like menin inhibitors is expected to drive further progress in the coming years.</p><p>On the basis of these impressive therapeutic advances, one might conclude that hematology is on track to achieve its goal, moving toward the cure or chronic management of most HMs. However, this conclusion warrants reconsideration. The ultimate objective of hematology should not be limited to improve survival, but also to reduce the burden of diseases in the overall population.</p><p>From this perspective, epidemiological data paint a more sobering picture. According to SEER data, which are adjusted on age and population size, disease-specific mortality has declined between 1975 and 2022 for HL (−80%), childhood leukemia (−73%), CML (−71%), ALL (−41%), CLL (−23%), and NHL (−16%). In contrast, mortality has remained relatively stable for MM (−3%) and AML (+4%) (Figure 1B). These trends appear inconsistent with major therapeutic advances observed over the same period.</p><p>This apparent paradox can largely be explained by concurrent changes in disease incidence. The age-adjusted SEER data show that, with the exception of HL, whose incidence is decreasing since 1975 (−27%), and CML, whose incidence is stable (−2%), all other HM are more frequent in 2022: AML (+21%), childhood leukemia (+22%), CLL (+26%), MM (+43%), ALL (+58%), and NHL (+69%) (Figure 1C).</p><p>When incidence and mortality are considered jointly, five distinct epidemiological patterns emerge (Figure 2). The most favorable pattern—declin","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 8","pages":""},"PeriodicalIF":11.3,"publicationDate":"2026-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70447","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148662502","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clonal and genomic determinants of e1a2 BCR::ABL1 chronic myeloid leukemia: A Fi-LMC study","authors":"Benjamin Podvin,&nbsp;Olivier Nibourel,&nbsp;Sandrine Hayette,&nbsp;Valérie Coiteux,&nbsp;Rathana Kim,&nbsp;Lucie Rigolot,&nbsp;Stéphanie Dulucq,&nbsp;Augustin Boudry,&nbsp;Geoffrey Pawlak,&nbsp;Wayne-Corentin Lambert,&nbsp;Pascale Flandrin-Gresta,&nbsp;Ivan Sloma,&nbsp;Christophe Roumier,&nbsp;Marie Balsat,&nbsp;Sandrine Loron,&nbsp;Chloé Li,&nbsp;Sandrine Geffroy,&nbsp;Jean-Michel Cayuela,&nbsp;Françoise Huguet,&nbsp;François-Xavier Mahon,&nbsp;Franck E. Nicolini,&nbsp;Delphine Réa,&nbsp;Claude Preudhomme,&nbsp;Nicolas Duployez,&nbsp;Catherine Roche-Lestienne,&nbsp;Fi-LMC group","doi":"10.1002/hem3.70454","DOIUrl":"https://doi.org/10.1002/hem3.70454","url":null,"abstract":"<p>The rarer p190 (e1a2) transcript in chronic myeloid leukemia (CML) is associated with atypical presentations; yet, its biological basis remains poorly understood. Using a cohort of 60 patients including 42 chronic phase patients age-matched 1:1 with 42 e13a2/e14a2 patients in the chronic phase, we investigated the clinical, genomic, and clonal features of e1a2 <i>BCR::ABL1</i> CML. We identified 60 e1a2 <i>BCR::ABL1</i> CML patients showing distinctive hematologic features including lower leukocyte and platelet counts and higher monocytosis (12.3% vs. 2.0%, P &lt; 0.001). Additional somatic mutations were detected in 37/42 (88%) e1a2 BCR::ABL1 cases compared with 7/42 (17%) e13a2/e14a2 <i>BCR::ABL1</i> cases. The mutational spectrum was dominated by <i>ASXL1</i> and <i>TET2</i>, and closely resembled CMML-like profiles. Genomic breakpoint sequences of 34 e1a2 <i>BCR::ABL1</i> cases showed that <i>BCR</i> and <i>ABL1</i> coordinates were similar to those observed in 394 B-ALL. Longitudinal mutational tracking revealed two distinct clonal architectures. In 71% of patients, mutations disappeared with molecular response, consistent with <i>BCR::ABL1</i> as the founding event. In contrast, 29% of patients had mutations with stable VAFs, while <i>BCR::ABL1</i> transcript levels decreased after treatment, indicating that the fusion had been acquired within a pre-existing mutated clone. Single-cell genotyping experiments confirmed these clonal architectures. These patients frequently developed cytopenias under tyrosine kinase inhibitor therapy and half required red blood cell transfusions, reflecting persistence of the ancestral clone rather than <i>BCR::ABL1</i>-driven disease. These findings show that e1a2 <i>BCR::ABL1</i> CML frequently arises within complex, premutated clonal backgrounds, providing a biological basis for its atypical presentation and heterogeneous treatment response.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 8","pages":""},"PeriodicalIF":11.3,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70454","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148662138","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Shooting the messenger: Ecosystem approaches in haematology","authors":"Stephen P. Hibbs","doi":"10.1002/hem3.70444","DOIUrl":"https://doi.org/10.1002/hem3.70444","url":null,"abstract":"&lt;p&gt;Treatment breakthroughs often take indirect pathways. Instead of targeting the affected cell or gene, bispecific antibodies redirect endogenous T-cells towards malignant B-cell lines, and gene therapy for sickle cell disease drastically upregulates production of fetal hemoglobin. Some cancer treatments act on non-human intermediaries: antibiotics against &lt;i&gt;Helicobacter pylori&lt;/i&gt; or direct-acting antivirals against the hepatitis C virus can induce remissions in some cases of marginal zone lymphoma.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;This article surveys two emerging treatment approaches directed to contrasting haematological clinical problems—dengue haemorrhagic fever and graft-vs-host-disease (GvHD)—acting on the wider ecosystems in which these conditions emerge. Beyond discovering novel treatment options, understanding haematological conditions through an ecological lens will become indispensable as the human-induced climate crisis unfolds.&lt;/p&gt;&lt;p&gt;Could an arthropod sexually transmitted infection be part of the treatment arsenal for a disease of haematological significance? &lt;i&gt;Aedes aegypti&lt;/i&gt; is the mosquito vector for viral diseases including dengue, Zika, chikungunya, and yellow fever. Each of these viruses can cause haematological complications; dengue can cause profound thrombocytopenia, coagulopathy, and bleeding complications. For decades, dengue transmission has been disrupted through insecticides and repellants, but these strategies are only partially effective.&lt;/p&gt;&lt;p&gt;A counterintuitive approach is to reduce the viability of &lt;i&gt;A. aegypti&lt;/i&gt; by infecting mosquitoes with &lt;i&gt;Wolbachia pipientis&lt;/i&gt;—sexually transmitted bacteria—which reduces the viability of mosquito offspring. There are many ways to deploy this technique, and one of the most effective is known as the incompatible insect technique–sterile insect technique (IIT-SIT). IIT-SIT involves sex-selecting male mosquitoes, infecting these mosquitoes with &lt;i&gt;W. pipientis&lt;/i&gt;, and finally irradiating to ensure any mis-sorted female mosquitoes are infertile. These infected mosquitoes are released to breed with wild-type females, but due to incompatibility between Wolbachia-infected and -uninfected mosquitoes, the offspring are not viable. This approach has not previously been trialed at scale.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Lim et al. conducted a cluster randomised trial of IIT-SIT to test whether this approach could reduce dengue incidence.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; The trial took place across regions of Singapore in which over 10% of the population live. In clusters receiving repeated IIT-SIT releases over a 2-year period, the &lt;i&gt;A. aegypti&lt;/i&gt; mosquito population fell almost sevenfold compared to control clusters. More importantly, residents living within intervention clusters were 70% less likely to contract symptomatic dengue virus.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; If dengue complications such as coagulopathy and thrombocytopenia are also reduced—a likely but unreported result of this i","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 8","pages":""},"PeriodicalIF":11.3,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70444","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148662139","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Passenger variants as pan-clonal markers of pediatric AML: Implications for molecular MRD","authors":"Ruth Shiloh,&nbsp;Dana Dayan,&nbsp;Ifat Geron,&nbsp;Maor Cohen,&nbsp;Tamar Feuerstein,&nbsp;Jorge Cano-Nistal,&nbsp;Nurit Gal-Mark,&nbsp;Shlomit Barzilai-Birenboim,&nbsp;Dafna Gaash,&nbsp;Michal Hameiri-Grossman,&nbsp;Avraham Kahan,&nbsp;Jamal Mahajna,&nbsp;Nino Oniashvili,&nbsp;Hava Rosenfeld,&nbsp;Dan Scharf,&nbsp;Keren Shichrur,&nbsp;Elena Shinderman-Maman,&nbsp;Sarah Elitzur,&nbsp;Yehudit Birger,&nbsp;Shai Izraeli,&nbsp;Yosef E. Maruvka","doi":"10.1002/hem3.70424","DOIUrl":"https://doi.org/10.1002/hem3.70424","url":null,"abstract":"<p>A streamlined, sensitive, and universal molecular method for MRD detection in pediatric AML remains an unmet clinical need. Here, we propose a novel approach based on tracking somatic non-coding passenger variants. Using whole-genome sequencing (WGS) of diagnostic bone marrow DNA, we identify patient-specific somatic passenger variants, which we term “leukemia-specific passenger variants” (LSPVs). Single-cell DNA proteogenomic analyses demonstrate that LSPVs are specific and robust markers of leukemic cells, present across the entire leukemic cell population. Moreover, we show that LSPVs are accurate markers of disease burden, stable from diagnosis to relapse. Importantly, LSPVs can be detected in all patients, suggesting the universal applicability of this approach. Leveraging these findings, we developed DAISY-MRD, a streamlined WGS-based MRD method that does not rely on the presence of specific trackable genetic aberrations and does not require tailored assay design, making it simple, efficient, and feasible in clinical settings.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 8","pages":""},"PeriodicalIF":11.3,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70424","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148662135","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clonal and genomic determinants of e1a2 BCR::ABL1 chronic myeloid leukemia: A Fi-LMC study","authors":"Benjamin Podvin,&nbsp;Olivier Nibourel,&nbsp;Sandrine Hayette,&nbsp;Valérie Coiteux,&nbsp;Rathana Kim,&nbsp;Lucie Rigolot,&nbsp;Stéphanie Dulucq,&nbsp;Augustin Boudry,&nbsp;Geoffrey Pawlak,&nbsp;Wayne-Corentin Lambert,&nbsp;Pascale Flandrin-Gresta,&nbsp;Ivan Sloma,&nbsp;Christophe Roumier,&nbsp;Marie Balsat,&nbsp;Sandrine Loron,&nbsp;Chloé Li,&nbsp;Sandrine Geffroy,&nbsp;Jean-Michel Cayuela,&nbsp;Françoise Huguet,&nbsp;François-Xavier Mahon,&nbsp;Franck E. Nicolini,&nbsp;Delphine Réa,&nbsp;Claude Preudhomme,&nbsp;Nicolas Duployez,&nbsp;Catherine Roche-Lestienne,&nbsp;Fi-LMC group","doi":"10.1002/hem3.70454","DOIUrl":"https://doi.org/10.1002/hem3.70454","url":null,"abstract":"<p>The rarer p190 (e1a2) transcript in chronic myeloid leukemia (CML) is associated with atypical presentations; yet, its biological basis remains poorly understood. Using a cohort of 60 patients including 42 chronic phase patients age-matched 1:1 with 42 e13a2/e14a2 patients in the chronic phase, we investigated the clinical, genomic, and clonal features of e1a2 <i>BCR::ABL1</i> CML. We identified 60 e1a2 <i>BCR::ABL1</i> CML patients showing distinctive hematologic features including lower leukocyte and platelet counts and higher monocytosis (12.3% vs. 2.0%, P &lt; 0.001). Additional somatic mutations were detected in 37/42 (88%) e1a2 BCR::ABL1 cases compared with 7/42 (17%) e13a2/e14a2 <i>BCR::ABL1</i> cases. The mutational spectrum was dominated by <i>ASXL1</i> and <i>TET2</i>, and closely resembled CMML-like profiles. Genomic breakpoint sequences of 34 e1a2 <i>BCR::ABL1</i> cases showed that <i>BCR</i> and <i>ABL1</i> coordinates were similar to those observed in 394 B-ALL. Longitudinal mutational tracking revealed two distinct clonal architectures. In 71% of patients, mutations disappeared with molecular response, consistent with <i>BCR::ABL1</i> as the founding event. In contrast, 29% of patients had mutations with stable VAFs, while <i>BCR::ABL1</i> transcript levels decreased after treatment, indicating that the fusion had been acquired within a pre-existing mutated clone. Single-cell genotyping experiments confirmed these clonal architectures. These patients frequently developed cytopenias under tyrosine kinase inhibitor therapy and half required red blood cell transfusions, reflecting persistence of the ancestral clone rather than <i>BCR::ABL1</i>-driven disease. These findings show that e1a2 <i>BCR::ABL1</i> CML frequently arises within complex, premutated clonal backgrounds, providing a biological basis for its atypical presentation and heterogeneous treatment response.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 8","pages":""},"PeriodicalIF":11.3,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70454","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148662137","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Passenger variants as pan-clonal markers of pediatric AML: Implications for molecular MRD","authors":"Ruth Shiloh,&nbsp;Dana Dayan,&nbsp;Ifat Geron,&nbsp;Maor Cohen,&nbsp;Tamar Feuerstein,&nbsp;Jorge Cano-Nistal,&nbsp;Nurit Gal-Mark,&nbsp;Shlomit Barzilai-Birenboim,&nbsp;Dafna Gaash,&nbsp;Michal Hameiri-Grossman,&nbsp;Avraham Kahan,&nbsp;Jamal Mahajna,&nbsp;Nino Oniashvili,&nbsp;Hava Rosenfeld,&nbsp;Dan Scharf,&nbsp;Keren Shichrur,&nbsp;Elena Shinderman-Maman,&nbsp;Sarah Elitzur,&nbsp;Yehudit Birger,&nbsp;Shai Izraeli,&nbsp;Yosef E. Maruvka","doi":"10.1002/hem3.70424","DOIUrl":"https://doi.org/10.1002/hem3.70424","url":null,"abstract":"<p>A streamlined, sensitive, and universal molecular method for MRD detection in pediatric AML remains an unmet clinical need. Here, we propose a novel approach based on tracking somatic non-coding passenger variants. Using whole-genome sequencing (WGS) of diagnostic bone marrow DNA, we identify patient-specific somatic passenger variants, which we term “leukemia-specific passenger variants” (LSPVs). Single-cell DNA proteogenomic analyses demonstrate that LSPVs are specific and robust markers of leukemic cells, present across the entire leukemic cell population. Moreover, we show that LSPVs are accurate markers of disease burden, stable from diagnosis to relapse. Importantly, LSPVs can be detected in all patients, suggesting the universal applicability of this approach. Leveraging these findings, we developed DAISY-MRD, a streamlined WGS-based MRD method that does not rely on the presence of specific trackable genetic aberrations and does not require tailored assay design, making it simple, efficient, and feasible in clinical settings.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 8","pages":""},"PeriodicalIF":11.3,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70424","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148662286","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Shooting the messenger: Ecosystem approaches in haematology","authors":"Stephen P. Hibbs","doi":"10.1002/hem3.70444","DOIUrl":"https://doi.org/10.1002/hem3.70444","url":null,"abstract":"&lt;p&gt;Treatment breakthroughs often take indirect pathways. Instead of targeting the affected cell or gene, bispecific antibodies redirect endogenous T-cells towards malignant B-cell lines, and gene therapy for sickle cell disease drastically upregulates production of fetal hemoglobin. Some cancer treatments act on non-human intermediaries: antibiotics against &lt;i&gt;Helicobacter pylori&lt;/i&gt; or direct-acting antivirals against the hepatitis C virus can induce remissions in some cases of marginal zone lymphoma.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;This article surveys two emerging treatment approaches directed to contrasting haematological clinical problems—dengue haemorrhagic fever and graft-vs-host-disease (GvHD)—acting on the wider ecosystems in which these conditions emerge. Beyond discovering novel treatment options, understanding haematological conditions through an ecological lens will become indispensable as the human-induced climate crisis unfolds.&lt;/p&gt;&lt;p&gt;Could an arthropod sexually transmitted infection be part of the treatment arsenal for a disease of haematological significance? &lt;i&gt;Aedes aegypti&lt;/i&gt; is the mosquito vector for viral diseases including dengue, Zika, chikungunya, and yellow fever. Each of these viruses can cause haematological complications; dengue can cause profound thrombocytopenia, coagulopathy, and bleeding complications. For decades, dengue transmission has been disrupted through insecticides and repellants, but these strategies are only partially effective.&lt;/p&gt;&lt;p&gt;A counterintuitive approach is to reduce the viability of &lt;i&gt;A. aegypti&lt;/i&gt; by infecting mosquitoes with &lt;i&gt;Wolbachia pipientis&lt;/i&gt;—sexually transmitted bacteria—which reduces the viability of mosquito offspring. There are many ways to deploy this technique, and one of the most effective is known as the incompatible insect technique–sterile insect technique (IIT-SIT). IIT-SIT involves sex-selecting male mosquitoes, infecting these mosquitoes with &lt;i&gt;W. pipientis&lt;/i&gt;, and finally irradiating to ensure any mis-sorted female mosquitoes are infertile. These infected mosquitoes are released to breed with wild-type females, but due to incompatibility between Wolbachia-infected and -uninfected mosquitoes, the offspring are not viable. This approach has not previously been trialed at scale.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Lim et al. conducted a cluster randomised trial of IIT-SIT to test whether this approach could reduce dengue incidence.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; The trial took place across regions of Singapore in which over 10% of the population live. In clusters receiving repeated IIT-SIT releases over a 2-year period, the &lt;i&gt;A. aegypti&lt;/i&gt; mosquito population fell almost sevenfold compared to control clusters. More importantly, residents living within intervention clusters were 70% less likely to contract symptomatic dengue virus.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; If dengue complications such as coagulopathy and thrombocytopenia are also reduced—a likely but unreported result of this i","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 8","pages":""},"PeriodicalIF":11.3,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70444","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148662287","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Macrocytosis combined with monoclonal gammopathy identifies patients carrying VEXAS-linked UBA1 mutations","authors":"Verena Petzer,&nbsp;Wolfram Mayr,&nbsp;Eva Spoegler,&nbsp;Emina Jukic,&nbsp;Christoph Winkler,&nbsp;Verena Vogi,&nbsp;Normann Steiner,&nbsp;Christina Duftner,&nbsp;Andrea Griesmacher,&nbsp;Günter Weiss,&nbsp;Dominik Wolf,&nbsp;Florian Kocher,&nbsp;David Haschka","doi":"10.1002/hem3.70441","DOIUrl":"https://doi.org/10.1002/hem3.70441","url":null,"abstract":"&lt;p&gt;Since the first description of VEXAS syndrome in 2020,&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; an inflammatory disease caused by somatic mutations of the &lt;i&gt;UBA1&lt;/i&gt; gene has gained increasing attention. Although the prevalence of &lt;i&gt;UBA1&lt;/i&gt; mutations has been estimated at approximately 1:4000 males &gt;50 years,&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; diagnosis remains challenging due to the highly heterogeneous clinical presentation and difficulties in preselection of patients for targeted molecular testing. This particularly holds true in patients with mild or atypical symptoms. Consistently, &lt;i&gt;UBA1&lt;/i&gt; mutations—initially considered pathognomonic for VEXAS—may show incomplete penetrance, particularly at low variant allele frequencies (VAFs), and can occur without overt inflammation.&lt;span&gt;&lt;sup&gt;3, 4&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;From a hematologic perspective, myelodysplastic neoplasms (MDS) are observed in up to 50% of patients with VEXAS,&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; and plasma cell dyscrasias have emerged as another common comorbidity, reported in approximately 20% of cases.&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; In addition, macrocytosis is a near-universal finding associated with VEXAS syndrome and was already highlighted in the initial report.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Maeda et al. further emphasized the significance of macrocytosis by creating a clinical scoring system in which macrocytic anemia uniquely received a two-point weighting, while all other parameters were assigned single points.&lt;span&gt;&lt;sup&gt;7&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;In this study, we aimed to evaluate the frequency of &lt;i&gt;UBA1&lt;/i&gt; mutations in the presence or absence of macrocytosis in male patients with concomitant monoclonal gammopathy (MG).&lt;/p&gt;&lt;p&gt;Therefore, we retrospectively identified 1245 patients with MG. Next, we excluded female patients (&lt;i&gt;n&lt;/i&gt; = 624), male patients with missing MCV data or if they were still alive (&lt;i&gt;n&lt;/i&gt; = 395), and a residual bone marrow (BM) aspirate sample was missing (&lt;i&gt;n&lt;/i&gt; = 36). Moreover, &lt;i&gt;n&lt;/i&gt; = 31 males were excluded as they either received an allo-HSCT or MG was most likely therapy-induced (monoclonal antibody, i.e., anti-CD38 therapy). After applying these exclusion criteria, &lt;i&gt;n&lt;/i&gt; = 160 patients were included in the final analysis (Figure 1A). The study was approved by the local ethics committee (No. 1194/2023). All analyses were performed in R statistical software (version 4.5.0), with a two-sided significance threshold of P &lt; 0.05. Further details are provided in the Supplemental Data file.&lt;/p&gt;&lt;p&gt;The patients were then stratified according to their mean corpuscular volume (MCV) as normocytic (MCV &lt; 96 fL, MG&lt;sup&gt;NORM&lt;/sup&gt;, &lt;i&gt;n&lt;/i&gt; = 65) or macrocytic (MCV ≥ 96 fL, MG&lt;sup&gt;MAC&lt;/sup&gt;, &lt;i&gt;n&lt;/i&gt; = 95) at the time of MG diagnosis (Figure 1A,B). MG&lt;sup&gt;MAC&lt;/sup&gt; were significantly older (median 70 years, interquartile range [IQR] 61–78) when compared to the MG&lt;sup&gt;NORM&lt;/sup&gt; cohort (median 65 years, IQR 57–74, P = 0.015). The median time interval between the initial diagnosis of the ","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 7","pages":""},"PeriodicalIF":11.3,"publicationDate":"2026-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70441","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148616216","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rab GTPases drive ligand-independent NOTCH1 activation via altered endocytic trafficking in chronic lymphocytic leukemia","authors":"Filomena De Falco,&nbsp;Beatrice Del Papa,&nbsp;Daniele Sorcini,&nbsp;Letizia Valmarini,&nbsp;Francesco Maria Adamo,&nbsp;Andrea Atzeni,&nbsp;Angela Esposito,&nbsp;Estevão Carlos Silva Barcelos,&nbsp;Erica Dorillo,&nbsp;Arianna Stella,&nbsp;Roberta Arcaleni,&nbsp;Fabio Gurrieri,&nbsp;Miriam Pugliese,&nbsp;Gabriele Astolfi,&nbsp;Maria Paola Martelli,&nbsp;Mauro Di Ianni,&nbsp;Emanuela Rosati,&nbsp;Paolo Sportoletti","doi":"10.1002/hem3.70440","DOIUrl":"https://doi.org/10.1002/hem3.70440","url":null,"abstract":"<p>Clinically relevant NOTCH1 activation is frequently observed in chronic lymphocytic leukemia (CLL), even in the absence of gene mutations, raising questions about the underlying mechanisms. In CLL cells, NOTCH1 activation may occur through mutation-independent mechanisms involving ligand interaction or cell-intrinsic, ligand-independent pathways that are not yet fully elucidated. To explore ligand-independent activation, we examined the involvement of NOTCH1 endocytic trafficking in generating the active intracellular domain (N1-ICD) in CLL cells. Using proximity ligation assay, we demonstrated that the NOTCH1 extracellular domain (N1-ECD), transmembrane subunit (N1-TM), and N1-ICD colocalize with Rab5 and Rab7, indicating NOTCH1 internalization and cleavage within endosomal compartments. Experiments with the endocytosis inhibitor Pitstop-2 demonstrated that NOTCH1 internalization is essential for N1-ICD generation. We provided evidence that N1-ICD generation occurs in Rab5 and Rab7 endosomal membranes. Treatment with chloroquine reduced N1-ICD, due to impaired endosomal acidification affecting enzymatic activity. Presenilin-1, the catalytic subunit of the γ-secretase complex responsible for N1-ICD generation, was found in early endosome compartments and colocalized with Rab5, Rab7, N1-TM, and N1-ICD. CLL cells expressing N1-ICD showed higher Rab5, Rab7, and presenilin-1 levels, increased Rab5 membrane association, and presenilin-1 activity versus N1-ICD-negative cells which showed increased lysosomal targeting. Silencing Rab5 or Rab7 by siRNA, or inhibiting Rab prenylation with psoromic acid, led to reduced N1-ICD levels and increased apoptosis in CLL cells. Interestingly, NOTCH1-mutated cases showed similar NOTCH1 trafficking. These findings identify for the first time a Rab-dependent endocytic trafficking as a key regulator of NOTCH1 activation and a potential therapeutic target in CLL.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 7","pages":""},"PeriodicalIF":11.3,"publicationDate":"2026-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70440","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148616215","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transplant versus no transplant outcome in adolescents and adults with sickle cell disease eligible for allogeneic hematopoietic stem cell transplantation","authors":"Cécile Pivert,&nbsp;Loïc Vasseur,&nbsp;Matthieu Jestin,&nbsp;Edouard Flamarion,&nbsp;Corinne Guitton,&nbsp;Maryse Etienne-Julan,&nbsp;Abdourahim Chamouine,&nbsp;Laurent Cimasoni,&nbsp;Claire Dichamp,&nbsp;Annie Kamden,&nbsp;Cécile Arnaud,&nbsp;Isabelle Genty,&nbsp;Marie Lagarde,&nbsp;Florence Rabian,&nbsp;Aude M. Fourmont,&nbsp;Florian Chevillon,&nbsp;Bichr Allaf,&nbsp;Laurie Toullec,&nbsp;Jean-Benoît Arlet,&nbsp;Nicolas Boissel,&nbsp;Corinne Pondarré,&nbsp;Nathalie Dhedin","doi":"10.1002/hem3.70434","DOIUrl":"10.1002/hem3.70434","url":null,"abstract":"<p>Hematopoietic stem cell transplantation (HSCT) remains the only curative option for sickle cell disease (SCD), but its use in adolescents and adults is limited by toxicity concerns. We evaluated the risk–benefit profile of HSCT in this population through a comparative analysis of transplant versus nontransplant strategies. HSCT was analyzed as a time-dependent variable in consecutive adolescents and adults with an indication for transplantation who were referred for HSCT counseling. At the last follow-up, patients had either undergone HSCT or not. HSCT procedures involved matched related donor (MRD) transplants after myeloablative or non-myeloablative conditioning, and haploidentical transplants after reduced-intensity conditioning. The primary endpoints were overall survival (OS) and composite event-free survival (cEFS), calculated from the initial consultation. Events included death, grade III–IV acute or moderate-to-severe chronic graft-versus-host disease (GVHD), graft rejection, overt stroke, third hospitalized painful crises within two years, acute chest syndrome (ACS), delayed hemolytic transfusion reaction, or initiation of new SCD modifying therapy. Ninety-four patients were included (median follow-up: 2.9 years), of whom 58 underwent HSCT. The 2-year OS was 98% with HSCT versus (vs.) 97% without HSCT (P = 0.55). cEFS was significantly higher post-transplant (72% vs. 28%, P &lt; 0.0001), with marked reduction in painful crises and ACS. Among patients who underwent transplantation, the 2-year rejection-free survival from the time of transplant was 91% for MRD and 82% for haploidentical HSCT (P = 0.40). HSCT substantially improves cEFS without excess short-term mortality, supporting its broader use in adolescents and adults with SCD, particularly when an MRD is available.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 7","pages":""},"PeriodicalIF":11.3,"publicationDate":"2026-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13390738/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148561846","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}