HemaSphere最新文献

{"title":"Waiting and seeing: The importance of long-term system-wide monitoring of mouse models of disease","authors":"David G. Kent","doi":"10.1002/hem3.70087","DOIUrl":"10.1002/hem3.70087","url":null,"abstract":"<p>Researchers undertaking complex in vivo research ranging from assessing hematopoietic stem cell (HSC) function to complex disease modeling are all too familiar with the pressures to find a phenotype and publish the resulting data as soon as possible. Moreover, the vagaries of the academic system are such that the individual driving the project is also often under pressure to deliver the first story and move on to the next project, making it doubly difficult to delve deeper into the biology of a specific mouse model. Therefore, the field has many exciting mouse models where only the surface has been scratched with respect to the biological function of a particular mutation. Running counter to this is a recent paper in <i>HemaSphere</i><span><sup>1</sup></span> from the McKinney-Freeman lab that explores a mouse model of G-protein-coupled receptor-associated sorting proteins (GPRASPs) longitudinally for its wider effects on the hematopoietic system. The paper “GPRASP protein deficiency triggers lymphoproliferative disease by affecting B-cell differentiation”<span><sup>1</sup></span> is a direct follow-up on the exciting story detailing GPRASP functional consequences in HSCs that appeared several years ago in <i>Blood</i>.<span><sup>2</sup></span> This new study in <i>HemaSphere</i> shows the power of undertaking detailed biological assessments of a mouse model beyond the initial findings in the area of research that a specific lab has expertise and is a great example of the power of fully characterizing and monitoring mouse models.</p><p>GPRASPs were identified as candidate molecules for altering HSC function due to their expression in long-term HSCs and evidence in other tissues of influencing and mediating microenvironmental changes. With previous functions highlighted in development and the maintenance of homeostasis, they represented strong targets for functional validation. The McKinney-Freeman lab took the first steps by individually silencing GPRASP family members in the setting of HSC transplantation to test whether GPRASP loss of function would enhance homing and function of HSCs. They showed increased survival, quiescence, migration, and homing and further went on to detail that GPRASPs were involved in the degradation of CXCR4, which meant that their removal increased the stability of CXCR4, a known regulator of HSC lodgement and homing in the adult bone marrow.<span><sup>2</sup></span> Notably, CXCR4 is the main chemokine receptor for stromal-derived factor 1 (SDF1), the key driver of the HSC chemotaxis that allows bone marrow homing to occur and is highly expressed on HSCs. That said, CXCR4 is also expressed in a range of other cells, and this is where the story gets interesting in this study.</p><p>Many researchers would have stopped the study here and moved on to a new model, but as shown in the recent issue of <i>HemaSphere</i>, Morales-Hernández has now followed up the mouse model and discovered another exciting role for GPRASPs","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 2","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11783231/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143079668","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":"Cytopenic overt primary myelofibrosis at presentation: Analysis of outcomes in the prospective, real-world ERNEST-2 registry","authors":"Paola Guglielmelli, Arianna Ghirardi, Alessandra Carobbio, Arianna Masciulli, Lucrezia Morrone, Barbara Mora, Elisa Rumi, Ana Triguero, Maria C. Finazzi, Helna Pettersson, Valentina Boldrini, Daniele Vanni, Alessandro Rambaldi, Francesco Passamonti, Alberto Alvarez-Larràn, Bjorn Andreasson, Alessandro M. Vannucchi, Tiziano Barbui","doi":"10.1002/hem3.70072","DOIUrl":"10.1002/hem3.70072","url":null,"abstract":"<p>Unlike polycythemia vera (PV), essential thrombocythemia (ET), and prefibrotic primary myelofibrosis (pre-PMF), which show variable expansion of myeloid cell lineages at diagnosis, overt primary myelofibrosis (PMF) may present with uni- or multi-lineage cytosis and isolated or multiple cytopenias, the latter feature configuring a “cytopenic” phenotype (CyP).<span><sup>1</sup></span> Among 1000 patients with PMF seen at Mayo Clinic, anemia and thrombocytopenia at diagnosis were found in 38%, including 24% requiring transfusions and 18%, respectively; those figures increased to 58%, 46%, and 28% for patients within 1 year from diagnosis.<span><sup>2</sup></span> Furthermore, cytopenias are exacerbated by treatments, including JAK inhibitors.<span><sup>3, 4</sup></span> Cytopenic MF is associated with a poorer prognosis compared to the “myeloproliferative” (MyP) counterpart and poses therapeutic challenges because of limited treatment options.<span><sup>5</sup></span> In the aforementioned study, overall survival (OS) was 7.9 years for patients without anemia compared to 4.9, 3.4, and 2.1 years, respectively, for patients with mild, moderate, and severe anemia. These findings were confirmed in other retrospective studies.<span><sup>6</sup></span> Also, isolated thrombocytopenia is prognostically adverse.<span><sup>7-9</sup></span> Anemia, especially if transfusion dependent, and thrombocytopenia, are individually enlisted in conventional risk scores for survival prediction,<span><sup>10-12</sup></span> including MIPSS70/v2.0 score,<span><sup>13-15</sup></span> and are associated with increased risk of blast phase (BP).<span><sup>16</sup></span></p><p>We report herein the analysis of data derived from the European multicenter collaborative ERNEST registry, specifically focusing on clinical characteristics and outcomes of MF patients with CyP. The ERNEST project prospectively enrolled patients with primary and secondary MF across tertiary European centers, with the aim of assuring reliability, representativeness, and comparability of real-world data. The project, promoted by the European LeukemiaNet (ELN) and coordinated by FROM (Research Foundation at Papa Giovanni XXIII Hospital in Bergamo), was supported by Novartis through a research collaboration. From February 2013 to May 2014, 1292 patients with WHO diagnosis of MF were included (ERNEST-1); for a subset of 584 overt PMF patients, enrolled in three countries (Italy, Spain, Sweden), extended follow-up data were available until the latest cutoff of December 2020 (ERNEST-2). The Institutional Review Board and Ethical Committee of each Centre approved the study, which was conducted in accordance with the Declaration of Helsinki. After the exclusion of 25 patients with incomplete data at diagnosis, a total of 559 patients constituted the current study population. A CyP was defined by the presence of at least one cytopenia at diagnosis: (i) sex-adjusted anemia (An), that is, hemoglobin (Hb) < 11","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 2","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11783225/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143079666","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":"Diagnosis and treatment of AML in the context of WHO and ICC 2022 classifications: Divergent nomenclature converges on common therapies","authors":"Uwe Platzbecker,&nbsp;Richard A. Larson,&nbsp;Sandeep Gurbuxani","doi":"10.1002/hem3.70083","DOIUrl":"10.1002/hem3.70083","url":null,"abstract":"<p>As a consequence of rapidly developing genetic technologies and advances in the understanding of the pathogenesis of acute myeloid leukemia (AML), the classification of AML has moved gradually from a morphologic and cytochemical-based system to one that is genetically defined. Recent molecular and genetic developments have been integrated into the diagnostic criteria for AML in the fifth edition of the World Health Organization (WHO) Classification of Haematolymphoid Tumours and the 2022 International Consensus Classification (ICC) of Myeloid Neoplasms and Acute Leukemias, expanding the list of genetically defined entities. In this review article, we use a case-based format describing the diagnostic workup, risk stratification, and possible treatment options to highlight the impact of the 2022 WHO and ICC classifications on clinical practice. We show that despite much commentary and anguish, there is a significant overlap between the two classifications. We further highlight the fact that even for entities with divergent nomenclature, such as <i>TP53</i>-mutated AML, the actual genetic lesion leads to convergent therapy.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 2","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11783223/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143079667","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":"Limited stage mantle cell lymphoma: A real-world study of primary treatment and prognosis in Sweden 2006–2018","authors":"Alexandra Albertsson-Lindblad,&nbsp;Sara Ekberg,&nbsp;Ingrid Glimelius,&nbsp;Fredrik Ellin,&nbsp;Kristina Sonnevi,&nbsp;Catharina Lewerin,&nbsp;Lena Brandefors,&nbsp;Karin E. Smedby,&nbsp;Mats Jerkeman","doi":"10.1002/hem3.70080","DOIUrl":"10.1002/hem3.70080","url":null,"abstract":"&lt;p&gt;Radiotherapy (RT) is an alternative to chemoimmunotherapy (CIT) in early-stage mantle cell lymphoma (MCL) as associated with activity and lower toxicity compared to CIT.&lt;span&gt;&lt;sup&gt;1-3&lt;/sup&gt;&lt;/span&gt; However, little is known how to stratify patients in relation to prognostic factors such as MCL International Prognostic Index (MIPI) and high-risk biology.&lt;span&gt;&lt;sup&gt;4-7&lt;/sup&gt;&lt;/span&gt; Here, we present overall (OS) and progression-free survival (PFS) in relation to prognostic factors and given treatment in a population-based cohort of patients diagnosed with stage I–II MCL in Sweden 2006–2018.&lt;/p&gt;&lt;p&gt;The study included all patients diagnosed with MCL 2006–2018 in the Swedish Lymphoma Register (SLR).&lt;span&gt;&lt;sup&gt;8&lt;/sup&gt;&lt;/span&gt; Early-stage MCL was defined as nodal or extra-nodal stage I or II disease, based on radiology with computer or positron emission tomography (PET) scan, peripheral blood count, and bone marrow examination. Patients were followed up to April 20, 2022. Patient characteristics, treatment, response, and data on documented relapse or progression proved by either radiology and/or biopsy were retrieved from SLR and supplementary medical records review. Data for calculation of Charlson comorbidity index (CCI) and survival data were retrieved from the National Patient Register and the Swedish Population Register respectively.&lt;span&gt;&lt;sup&gt;9&lt;/sup&gt;&lt;/span&gt; Treatment was categorized as CIT, curative (≥24 Gy) or non-curative (&lt;24 Gy) RT, watch and wait, or as other/missing. CIT followed by RT was grouped with CIT. High-risk biology was defined as blastoid histology, Ki67 ≥ 30%, or p53 overexpression (OE). Comparison of variables between subgroups was performed by Student's &lt;i&gt;t&lt;/i&gt;-test, Mann–Whitney's test, or chi-square test. The Kaplan–Meier estimator was used for calculation of PFS and OS from end of first treatment if not otherwise specified until date of relapse or progression (PD) (PFS) or end of FU (OS + PFS). Hazard ratios (HRs) were estimated with Cox regression in univariable models by age, sex, ECOG, MIPI, stage, elevated lactate dehydrogenase (LDH), and RT ≥ 24 Gy and by multivariable models including variables with significant HRs (&lt;i&gt;p&lt;/i&gt; &lt; 0.05) in univariable analysis. Stata SE 16.1 was used for all analysis. The study was approved by the Regional Board of the Ethical Committee in Lund, Sweden (2018/739).&lt;/p&gt;&lt;p&gt;In total, 1412 MCL patients were identified, of which 173 (13%) fulfilled criteria for stage I–II disease. Out of stage I-II, PET-scan was used for staging in 8% and 22 (13%) patients had extra-nodal disease. Data on high-risk biology was available in 66 (64%) patients, of whom 30 (45%) had at least one high-risk biology marker. Stage I–II patients had lower MIPI, less frequently B symptoms, and elevated LDH compared to stage III–IV (Supporting Information S1: Table 1). Stage I (&lt;i&gt;n&lt;/i&gt; = 72) patients were of lower age and blastoid MCL was less frequent compared to stage II (&lt;i&gt;n&lt;/i&gt; = 101), but similar in B symptoms, ","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11770327/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143052295","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":"sMAdCAM-1 is decreased after allo-HCT, along with gut microbiota dysbiosis, and is associated with hematopoietic recovery","authors":"Karen Fadel,&nbsp;Lama Siblany,&nbsp;Razan Mohty,&nbsp;Nicolas Stocker,&nbsp;Ludovic Suner,&nbsp;Eolia Brissot,&nbsp;Anne Banet,&nbsp;Simona Sestili,&nbsp;Rémy Duléry,&nbsp;Zoé Van de Wyngaert,&nbsp;Laure Ricard,&nbsp;Ramdane Belhocine,&nbsp;Agnès Bonnin,&nbsp;Antoine Capes,&nbsp;Tounes Ledraa,&nbsp;Frederic De Vassoigne,&nbsp;Harry Sokol,&nbsp;Mohamad Mohty,&nbsp;Béatrice Gaugler,&nbsp;Florent Malard","doi":"10.1002/hem3.70074","DOIUrl":"10.1002/hem3.70074","url":null,"abstract":"&lt;p&gt;Chemotherapy and total-body irradiation-based conditioning regimens, together with the use of broad-spectrum antibiotics during allogeneic hematopoietic cell transplantation (allo-HCT), induce gut microbiota dysbiosis,&lt;span&gt;&lt;sup&gt;1, 2&lt;/sup&gt;&lt;/span&gt; which is associated with poor patient outcomes.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Furthermore, it has been reported that the intestinal microbiome and the hematopoietic system interplay.&lt;span&gt;&lt;sup&gt;3, 4&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Fidelle et al. showed recently in a cohort of non-small cell lung cancer patients that antibiotic-induced dysbiosis led to the loss of MAdCAM-1 tissular expression and decreased soluble MadCAM-1 (sMAdCAM-1).&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; MAdCAM-1, expressed on endothelial cells, interacts with the α4β7 integrin to direct hematopoietic stem cell (HSC) homing and engraftment&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; and the trafficking of lymphocytes into Peyer's patches and the intestinal lamina propria.&lt;span&gt;&lt;sup&gt;7&lt;/sup&gt;&lt;/span&gt; It is established that the MAdCAM-1/α4β7 axis is implicated in the recruitment of effector donor CD8 T cells to the recipient intestine and that blocking this axis prevents graft-versus-host disease (GvHD).&lt;span&gt;&lt;sup&gt;8, 9&lt;/sup&gt;&lt;/span&gt; Altogether, this suggests that the interplay between the MAdCAM-1/α4β7 axis, the microbiota, and the use of antibiotics warrants investigation in the setting of allo-HCT. We, therefore, aimed to investigate the impact of sMAdCAM-1 level on patients' outcomes after allo-HCT, particularly GvHD and hematopoietic recovery.&lt;/p&gt;&lt;p&gt;This retrospective study comprised a cohort of 279 consecutive adult patients with a hematological malignancy who underwent allo-HCT between October 2012 and June 2018. Patient and disease characteristics are detailed in Table 1. Written informed consent was obtained from each patient in accordance with the principles of the Declaration of Helsinki. Sera were collected prior to allo-HCT (baseline timepoint), the day of allo-HCT (D0), and at D20, 90, and 360 after allo-HCT, and sMAdCAM-1 was quantified using the Human MAdCAM-1 DuoSet ELISA kit (Bio-Techne/R&amp;D Systems). Patients' supportive care (including infection prophylaxis), serum preparation and sMAdCAM-1 quantification, stool collection, DNA extraction and 16S sequencing, and analysis and statistical methods are listed in the Supporting Information File.&lt;/p&gt;&lt;p&gt;Because tissue biopsies are difficult to obtain and sMAdCAM-1 originates from cleavage of tissular MAdCAM-1, we evaluated sMAdCAM-1 concentrations in the blood using ELISA as a surrogate marker for tissular MadCAM-1 expression. sMAdCAM-1 levels significantly decreased following conditioning, reaching 4234 pg/mL at D0 versus 8815 pg/mL at baseline (&lt;i&gt;p&lt;/i&gt; &lt; 0.0001), and continued to decline to 3277 pg/mL by D20 (&lt;i&gt;p&lt;/i&gt; &lt; 0.0001). At D90 (&lt;i&gt;n&lt;/i&gt; = 221), while sMAdCAM-1 levels increased compared to D20, being 4275 pg/mL (&lt;i&gt;p&lt;/i&gt; &lt; 0.0001), it remained significantly lower compared to baseline samples (&lt;i&gt;p&lt;/i&gt; &lt","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11770326/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143052296","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":"Combining SKY92 gene expression profiling and FISH (according to R2-ISS) defines ultra-high-risk Multiple Myeloma","authors":"Xiang Zhou,&nbsp;Annika Hofmann,&nbsp;Benedict Engel,&nbsp;Cornelia Vogt,&nbsp;Silvia Nerreter,&nbsp;Yoko Tamamushi,&nbsp;Friederike Schmitt,&nbsp;Maria leberzammer,&nbsp;Emilia Stanojkovska,&nbsp;Marietta Truger,&nbsp;Xianghui Xiao,&nbsp;Christine Riedhammer,&nbsp;Maximilian J. Steinhardt,&nbsp;Mara John,&nbsp;Julia Mersi,&nbsp;Seungbin Han,&nbsp;Umair Munawar,&nbsp;Johannes M. Waldschmidt,&nbsp;Claudia Haferlach,&nbsp;Hermann Einsele,&nbsp;Leo Rasche,&nbsp;K. Martin Kortüm","doi":"10.1002/hem3.70078","DOIUrl":"10.1002/hem3.70078","url":null,"abstract":"<p>The definition of high-risk (HR) multiple myeloma (MM) is still a matter of debate. We prospectively evaluated the HR detection using FISH in combination with SKY92 gene expression profiling in 258 MM patients (newly diagnosed [ND] MM: <i>n</i> = 109; relapsed/refractory [RR] MM: <i>n</i> = 149). HR SKY92 was significantly enriched in RRMM (57/121, 47.1%) compared with NDMM (17/95, 17.9%) (<i>p</i> &lt; 0.0001). RRMM patients with HR SKY92 showed significantly shorter progression-free survival (PFS) (<i>p</i> &lt; 0.0001) and overall survival (OS) (<i>p</i> &lt; 0.0001) than SKY92 standard-risk (SR). In NDMM, HR SKY92 also indicated a significantly inferior PFS (<i>p</i> &lt; 0.0001) in comparison with SR. We combined SKY92 with FISH (HR: t(4;14), del17p, +1q21 according to R2-ISS) in 181 patients (NDMM: <i>n</i> = 79; RRMM: <i>n</i> = 102). We found a discrepancy between both risk stratification systems, with only 49 (27.1%) patients being defined as HR by both SKY92 and FISH (“double HR”). In terms of survival outcomes, “double HR” presented a negative prognostic factor for PFS in both NDMM (<i>p</i> &lt; 0.0001) and RRMM (<i>p</i> &lt; 0.0001). Furthermore, “double-HR” patients showed the worst OS (<i>p</i> = 0.000 13) in RRMM. Additionally, whole genome sequencing (WGS) revealed <i>CRBN</i> mutation (<i>n</i> = 3) and bi-allelic events (mutation and/or deletion) in <i>TP53</i> (<i>n</i> = 7) and <i>TNFRSF17</i> (<i>n</i> = 1). Altogether, we provide the first prospective real-world evidence that the combination SKY92 and FISH (according to R2-ISS) identifies a subset of patients with ultra-HR MM, and WGS complements SKY92 and FISH in MM risk stratification.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11754766/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143028704","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":"Somatic mutations and DNA methylation identify a subgroup of poor prognosis within lower-risk myelodysplastic syndromes","authors":"David Rombaut,&nbsp;Sarah Sandmann,&nbsp;Tobias Tekath,&nbsp;Simon Crouch,&nbsp;Aniek O. de Graaf,&nbsp;Alexandra Smith,&nbsp;Daniel Painter,&nbsp;Olivier Kosmider,&nbsp;Magnus Tobiasson,&nbsp;Andreas Lennartsson,&nbsp;Bert A. van der Reijden,&nbsp;Sophie Park,&nbsp;Maud D'Aveni,&nbsp;Borhane Slama,&nbsp;Emmanuelle Clappier,&nbsp;Pierre Fenaux,&nbsp;Lionel Adès,&nbsp;Arjan van de Loosdrecht,&nbsp;Saskia Langemeijer,&nbsp;Argiris Symeonidis,&nbsp;Jaroslav Čermák,&nbsp;Claude Preudhomme,&nbsp;Aleksandar Savic,&nbsp;Ulrich Germing,&nbsp;Reinhard Stauder,&nbsp;David Bowen,&nbsp;Corine van Marrewijk,&nbsp;Elsa Bernard,&nbsp;Theo de Witte,&nbsp;Julian Varghese,&nbsp;Eva Hellström-Lindberg,&nbsp;Martin Dugas,&nbsp;Joost Martens,&nbsp;Luca Malcovati,&nbsp;Joop H. Jansen,&nbsp;Michaela Fontenay,&nbsp;MDS-RIGHT consortium","doi":"10.1002/hem3.70073","DOIUrl":"10.1002/hem3.70073","url":null,"abstract":"<p>Lower risk (LR) myelodysplastic syndromes (MDS) are heterogeneous hematopoietic stem and progenitor disorders caused by the accumulation of somatic mutations in various genes including epigenetic regulators that may produce convergent DNA methylation patterns driving specific gene expression profiles. The integration of genomic, epigenomic, and transcriptomic profiling has the potential to spotlight distinct LR-MDS categories on the basis of pathophysiological mechanisms. We performed a comprehensive study of somatic mutations and DNA methylation in a large and clinically well-annotated cohort of treatment-naive patients with LR-MDS at diagnosis from the EUMDS registry (ClinicalTrials.gov.NCT00600860). Unsupervised clustering analyses identified six clusters based on genetic profiling that concentrate into four clusters on the basis of genome-wide methylation profiling with significant overlap between the two clustering modes. The four methylation clusters showed distinct clinical and genetic features and distinct methylation landscape. All clusters shared hypermethylated enhancers enriched in binding motifs for ETS and bZIP (C/EBP) transcription factor families, involved in the regulation of myeloid cell differentiation. By contrast, one cluster gathering patients with early leukemic evolution exhibited a specific pattern of hypermethylated promoters and, distinctly from other clusters, the upregulation of AP-1 complex members FOS/FOSL2 together with the absence of hypermethylation of their binding motif at target gene enhancers, which is of relevance for leukemic initiation. Among MDS patients with lower-risk IPSS-M, this cluster displayed a significantly inferior overall survival (<i>p</i> &lt; 0.0001). Our study showed that genetic and DNA methylation features of LR-MDS at early stages may refine risk stratification, therefore offering the frame for a precocious therapeutic intervention.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11754767/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143028735","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":"Prevalence of type I Gaucher disease in patients with smoldering or multiple myeloma: Results from the prospective, observational CHAGAL study","authors":"Sonia Morè,&nbsp;Irene Federici,&nbsp;Alessandra Bossi,&nbsp;Serena Rupoli,&nbsp;Erika Morsia,&nbsp;Valentina M. Manieri,&nbsp;Attilio Olivieri,&nbsp;Maria T. Petrucci,&nbsp;Francesca Fazio,&nbsp;Chiara Lisi,&nbsp;Silvia Sorella,&nbsp;Adele D. Paoli,&nbsp;Francesca Farina,&nbsp;Anna Mele,&nbsp;Rossella De Francesco,&nbsp;Antonino Greco,&nbsp;Francesca Fioritoni,&nbsp;Carmine Liberatore,&nbsp;Tommaso C. De Toritto,&nbsp;Attilio Tordi,&nbsp;Agostina Siniscalchi,&nbsp;Marino Brunori,&nbsp;Nicola Sgherza,&nbsp;Pellegrino Musto,&nbsp;Angela Amendola,&nbsp;Angelo Vacca,&nbsp;Antonio G. Solimando,&nbsp;Assunta Melaccio,&nbsp;Antonio Palma,&nbsp;Lorella M. A. Melillo,&nbsp;Lucia Ciuffreda,&nbsp;Silvia Gentili,&nbsp;Gabriele Buda,&nbsp;Maria L. Del Giudice,&nbsp;Antonietta P. Falcone,&nbsp;Patrizia Tosi,&nbsp;Simona Tomassetti,&nbsp;Francesco Rotondo,&nbsp;Alessandro Gozzetti,&nbsp;Piero Galieni,&nbsp;Miriana Ruggieri,&nbsp;Ferdinando Frigeri,&nbsp;Rosario Bianco,&nbsp;Alessandra Lombardo,&nbsp;Fabio Trastulli,&nbsp;Laura Corvatta,&nbsp;Carmela Zizzo,&nbsp;Giovanni Duro,&nbsp;Massimo Offidani","doi":"10.1002/hem3.70079","DOIUrl":"10.1002/hem3.70079","url":null,"abstract":"&lt;p&gt;Gaucher disease (GD) represents a lysosomal storage disease caused by a genetic defect of the enzyme β-glucocerebrosidase (GBA) involved in the breakdown of complex glycosphingolipids, which are important components of cell membranes. Deficient GBA enzyme activity causes the accumulation of substrate glucosylceramide in lysosomes of cells of the reticuloendothelial system and the characteristic macrophages loaded with glucosylceramide defined as “Gaucher cells.”&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Type 1 GD (GD1), affecting more than 90% of patients with GD from Europe and North America, can be diagnosed at any age since initial symptoms (fatigue, asthenia, bone pain) are nonspecific. The subsequent main clinical findings, such as bone disease, hepatosplenomegaly, anemia, thrombocytopenia, and coagulation abnormalities can be misdiagnosed, due to the rarity of the disease and heterogeneity of the clinical picture. Being inherited in an autosomal recessive manner, identification of biallelic pathogenic variants in &lt;i&gt;GBA1&lt;/i&gt; on molecular genetic test is required to confirm the diagnosis of GD1, besides glucocerebrosidase activity measurement in peripheral blood leukocytes. The incidence is associated with particular populations such as those of Ashkenazi Jewish descent among whom GD1 was estimated at 1 in 450 births. In contrast, in a recent review, the incidence was estimated at 0.45–22.9/100,000 live births in Europe and North America (4.5/100,000 live births in Italy). Estimated prevalence per 100,000 population was 0.26–0.63 in Europe.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Evidence has accumulated over time for a risk for multiple myeloma (MM) occurrence from 5.9 to 51.1 times greater in patients with GD1 compared to the general population.&lt;span&gt;&lt;sup&gt;3-5&lt;/sup&gt;&lt;/span&gt; However, no studies explored the concurrent GD1 in patients diagnosed with MM except a small retrospective study.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; Herein, we reported the results of a multicentre, observational, cross-sectional study, designed to evaluate the prevalence of GD1 in patients with smoldering MM (SMM) and newly diagnosed MM (NDMM) or relapsed/refractory MM (RRMM),&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; aged &gt;18 years giving written informed consent. The study was approved by the competent Ethics Committee for each center, and it was conducted in accordance with the Good Clinical Practice (ICH Harmonized Tripartite Guidelines for Good Clinical Practice 1996 Directive 91/507/EEC; D.M. 15.7.1997).&lt;/p&gt;&lt;p&gt;The primary aim of the study was the prevalence of unrecognized GD1 in a selected adult population with a confirmed diagnosis of SMM or MM. The secondary endpoint was to assess if, in patients with a final diagnosis of GD1, distinctive features could be identified to draw a diagnostic algorithm for early identification of genetic disease.&lt;/p&gt;&lt;p&gt;Peripheral blood of enrolled patients was drawn using EDTA as an anticoagulant, and it was applied to a specific adsorbent paper spot (dried blood spot, DBS) which","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11754764/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143028734","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":"Mastering fate: Redistributing a pioneer protein to rewrite leukemia's script","authors":"Yizhou Huang,&nbsp;Charles E. de Bock","doi":"10.1002/hem3.70084","DOIUrl":"10.1002/hem3.70084","url":null,"abstract":"&lt;p&gt;The pioneer transcription factor PU.1 plays a crucial role in hematopoiesis, particularly during myeloid and lymphoid differentiation. PU.1 dysregulation has been implicated in leukemia development, including acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). However, developing therapeutic agents that directly target transcription factors has been challenging. This is partly due to the lack of well-defined active sites amenable to pharmacological inhibition, making them undruggable and indispensable functions in healthy cells.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;In a new study led by Samuel Taylor in the laboratory of Ulrich Steidl, the authors took another approach to block PU.1 activity using a small molecule inhibitor that specifically blocked PU.1's interaction with DNA. Interestingly, rather than a global loss of PU.1 binding, the authors found that PU.1 was redistributed to alternative DNA sites within the genome, activating cellular differentiation.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; The implications of this therapeutic concept, particularly in relation to differentiation therapy, represent an important new development for the treatment of leukemia.&lt;/p&gt;&lt;p&gt;Unlike kinases or other enzymes, transcription factors lack catalytic domains that can be inhibited, making direct pharmacological intervention more challenging. The new agents used by Taylor et al. are DNA-binding heterocyclic diamidines, designed to specifically bind adenine–thymine (AT)-rich minor grooves at DNA sites targeted by PU.1, thereby inhibiting PU.1 binding. Treatment of AML cells with this class of agents (DB2115, DB2373, DB2826, and DB2313) resulted in a significant decrease in AML cell proliferation. Originally, the authors hypothesized that this was a consequence of drug-induced global loss of PU.1 binding across the genome. Surprisingly, they then found that not only did the vast majority of PU.1 sites remain unchanged after drug treatment, but there was nearly an equivalent loss and gain of PU.1 binding sites. Their data instead support a model in which PU.1 is redistributed to alternative genomic regions rather than global loss of binding (Figure 1).&lt;/p&gt;&lt;p&gt;To understand the molecular biology underlying this observation, the authors used numerous elegant sequencing techniques such as CLICK-on-CUT&amp;Tag, ATAC-sequencing, and ChIP-sequencing temporally to directly show where the drug bound, PU.1 was lost and chromatin then closed. Conversely, closed chromatin regions that gained PU.1 binding were remodeled to become more accessible. Using transcriptomics and gene set enrichment analysis, the authors showed that these gained PU.1-bound regions were involved in “cellular differentiation,” whereas the PU.1-lost regions were enriched for a “stem cell signature” (Figure 1). Hence, these drugs pharmacologically reprogrammed PU.1-mediated transcriptional activity to drive cellular differentiation instead of completely suppressing its activity. This represents a signific","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11754763/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143028625","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":"Detection of clinically relevant variants in the TP53 gene below 10% allelic frequency: A multicenter study by ERIC, the European Research Initiative on CLL","authors":"Sarka Pavlova,&nbsp;Jitka Malcikova,&nbsp;Lenka Radova,&nbsp;Silvia Bonfiglio,&nbsp;Jack B. Cowland,&nbsp;Christian Brieghel,&nbsp;Mette K. Andersen,&nbsp;Maria Karypidou,&nbsp;Bella Biderman,&nbsp;Michael Doubek,&nbsp;Gregory Lazarian,&nbsp;Inmaculada Rapado,&nbsp;Matthijs Vynck,&nbsp;Naomi A. Porret,&nbsp;Martin Andres,&nbsp;Dina Rosenberg,&nbsp;Dvora Sahar,&nbsp;Carolina Martínez-Laperche,&nbsp;Ismael Buño,&nbsp;Andrew Hindley,&nbsp;David Donaldson,&nbsp;Julio B. Sánchez,&nbsp;José A. García-Marco,&nbsp;Alicia Serrano-Alcalá,&nbsp;Blanca Ferrer-Lores,&nbsp;Concepción Fernández-Rodriguez,&nbsp;Beatriz Bellosillo,&nbsp;Stephan Stilgenbauer,&nbsp;Eugen Tausch,&nbsp;Hero Nikdin,&nbsp;Fiona Quinn,&nbsp;Emer Atkinson,&nbsp;Lisette van de Corput,&nbsp;Cafer Yildiz,&nbsp;Cristina Bilbao-Sieyro,&nbsp;Yanira Florido,&nbsp;Christian Thiede,&nbsp;Caroline Schuster,&nbsp;Anastazja Stoj,&nbsp;Sylwia Czekalska,&nbsp;Anastasia Chatzidimitriou,&nbsp;Stamatia Laidou,&nbsp;Audrey Bidet,&nbsp;Charles Dussiau,&nbsp;Friedel Nollet,&nbsp;Giovanna Piras,&nbsp;Maria Monne,&nbsp;Svetlana Smirnova,&nbsp;Eugene Nikitin,&nbsp;Ivan Sloma,&nbsp;Alexis Claudel,&nbsp;Laetitia Largeaud,&nbsp;Loïc Ysebaert,&nbsp;Peter J. M. Valk,&nbsp;Amy Christian,&nbsp;Renata Walewska,&nbsp;David Oscier,&nbsp;Marta Sebastião,&nbsp;Maria Gomes da Silva,&nbsp;Piero Galieni,&nbsp;Mario Angelini,&nbsp;Davide Rossi,&nbsp;Valeria Spina,&nbsp;Sónia Matos,&nbsp;Vânia Martins,&nbsp;Tomasz Stokłosa,&nbsp;Monika Pepek,&nbsp;Panagiotis Baliakas,&nbsp;Rafa Andreu,&nbsp;Irene Luna,&nbsp;Tiina Kahre,&nbsp;Ülle Murumets,&nbsp;Tereza Pikousova,&nbsp;Terezia Kurucova,&nbsp;Sophie Laird,&nbsp;Daniel Ward,&nbsp;Miguel Alcoceba,&nbsp;Ana Balanzategui,&nbsp;Lydia Scarfo,&nbsp;Francesca Gandini,&nbsp;Ettore Zapparoli,&nbsp;Adoración Blanco,&nbsp;Pau Abrisqueta,&nbsp;Ana E. Rodríguez-Vicente,&nbsp;Rocío Benito,&nbsp;Clotilde Bravetti,&nbsp;Frédéric Davi,&nbsp;Paula Gameiro,&nbsp;Joaquin Martinez-Lopez,&nbsp;Bárbara Tazón-Vega,&nbsp;Fanny Baran-Marszak,&nbsp;Zadie Davis,&nbsp;Mark Catherwood,&nbsp;Andrey Sudarikov,&nbsp;Richard Rosenquist,&nbsp;Carsten U. Niemann,&nbsp;Kostas Stamatopoulos,&nbsp;Paolo Ghia,&nbsp;Sarka Pospisilova","doi":"10.1002/hem3.70065","DOIUrl":"10.1002/hem3.70065","url":null,"abstract":"<p>In chronic lymphocytic leukemia, the reliability of next-generation sequencing (NGS) to detect <i>TP53</i> variants ≤10% allelic frequency (low-VAF) is debated. We tested the ability to detect 23 such variants in 41 different laboratories using their NGS method of choice. The sensitivity was 85.6%, 94.5%, and 94.8% at 1%, 2%, and 3% VAF cut-off, respectively. While only one false positive (FP) result was reported at &gt;2% VAF, it was more challenging to distinguish true variants &lt;2% VAF from background noise (37 FPs reported by 9 laboratories). The impact of low-VAF variants on time-to-second-treatment (TTST) and overall survival (OS) was investigated in a series of 1092 patients. Among patients not treated with targeted agents, patients with low-VAF <i>TP53</i> variants had shorter TTST and OS versus wt-<i>TP53</i> patients, and the relative risk of second-line treatment or death increased continuously with increasing VAF. Targeted therapy in ≥2 line diminished the difference in OS between patients with low-VAF <i>TP53</i> variants and wt-<i>TP53</i> patients, while patients with high-VAF <i>TP53</i> variants had inferior OS compared to wild type-<i>TP53</i> cases. Altogether, NGS-based approaches are technically capable of detecting low-VAF variants. No strict threshold can be suggested from a technical standpoint, laboratories reporting <i>TP53</i> mutations should participate in a standardized validation set-up. Finally, whereas low-VAF variants affected outcomes in patients receiving chemoimmunotherapy, their impact on those treated with novel therapies remains undetermined. Our results pave the way for the harmonized and accurate <i>TP53</i> assessment, which is indispensable for elucidating the role of <i>TP53</i> mutations in targeted treatment.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11746920/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143004481","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}