HemaSphere最新文献

{"title":"Expression profile of Bcl-2 family proteins in newly diagnosed multiple myeloma patients","authors":"Cristina De Ramón,&nbsp;Elizabeta A. Rojas,&nbsp;Irena Misiewicz-Krzeminska,&nbsp;Ignacio J. Cardona-Benavides,&nbsp;Myriam Cuadrado,&nbsp;Isabel Isidro,&nbsp;María-José Calasanz,&nbsp;Manuela Fernandez,&nbsp;Ramón García-Sanz,&nbsp;Noemi Puig,&nbsp;M. Teresa Cedena,&nbsp;Bruno Paiva,&nbsp;Laura Rosiñol,&nbsp;Joaquín Martínez-López,&nbsp;Joan Bladé,&nbsp;Juan J. Lahuerta,&nbsp;Jesús F. San Miguel,&nbsp;María V. Mateos,&nbsp;Luis A. Corchete,&nbsp;Norma C. Gutiérrez,&nbsp;GEM/PETHEMA cooperative study group","doi":"10.1002/hem3.70036","DOIUrl":"10.1002/hem3.70036","url":null,"abstract":"<p>Antiapoptotic Bcl-2 family proteins are involved in myeloma cell survival. To date, their expression in multiple myeloma (MM) patients has mostly been analyzed at the RNA level. In the present study, we quantified for the first time the protein expression of the Bcl2-family members using a capillary electrophoresis immunoassay in 120 newly diagnosed MM patients, aged ≤65 years, treated in the context of the PETHEMA/GEM2012 study. We found that the pattern of expression of Bcl-2 family proteins was highly heterogeneous among patients. Although cases with t(11;14) had significantly higher levels of Bcl-2/Bcl-xL and Bcl-2+Bim+Bax/Bcl-xL ratios than those without t(11;14), the presence of this translocation was not synonymous with such high levels of expression. Conversely, some patients with other genetic alterations also showed higher levels of those ratios. Survival analysis revealed that the high expression of Bad and Puma proteins was associated with significantly longer overall survival (<i>p</i> = 0.001 and <i>p</i> &lt; 0.001, respectively). Bcl-2 protein ratios predicting sensitivity to venetoclax <i>in vitro</i> were also able to distinguish patients with shorter time to progression after triplet-based induction therapy and ASCT. This is the first study to assess the expression of the most important Bcl-2 family proteins by a quantitative method in a large set of MM patients according to their cytogenetic abnormalities. We shed light on the impact of these proteins on MM prognosis, which could help to consider the levels of proteins involved in apoptosis in the development of new therapeutic strategies.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 12","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11645297/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142828239","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":"Novel approaches in myelofibrosis","authors":"Steffen Koschmieder","doi":"10.1002/hem3.70056","DOIUrl":"10.1002/hem3.70056","url":null,"abstract":"<p>Myelofibrosis (MF) is a clonal myeloid neoplasm characterized by bone marrow fibrosis, splenomegaly, and disease-associated symptoms, as well as increased mortality, due to thrombosis, severe bleeding, infections, or progression to acute leukemia. Currently, the management of MF patients is tailored according to risk scores, with higher-risk (intermediate-2 and high-risk) patients being assessed for allogeneic stem cell transplantation, which remains the only potentially curative treatment option. On the other hand, lower risk (low- and intermediate-1 risk) patients who are symptomatic may be treated with JAK inhibitors or other drugs. However, none of these drug treatments have induced relevant rates of durable complete remissions, and, therefore, novel treatments are needed to improve the long-term outcomes of MF patients. This review summarizes current preclinical and clinical approaches to MF therapy, including novel drug combinations involving JAK inhibitors and innovative monotherapies. These drugs target transcription, nuclear export, survival pathways, or various intracellular pathways, ranging from JAK-STAT signaling to PI3-Kinase, TP53, PIM1, or S100A8/A9/toll-like receptor pathways. Also, extracellular targeting using interferon, calreticulin mutant-specific antibodies, and other immunotherapeutic approaches are discussed, as well as various antifibrotic strategies. In addition, preclinical approaches that target individual mutated clones, for example, by mutation-specific JAK2V617F inhibitors or DNA repair pathway inhibitors, are presented. Finally, current efforts of generating novel endpoints for clinical trials aim more at disease modification and overall survival than at improvements of splenomegaly or symptoms. Together, the new generations of clinical trials promise to offer substantial improvements in the management of MF patients and long-term disease control.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 12","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11636632/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142817913","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":"Analysis of smoldering multiple myeloma according to the target of the monoclonal immunoglobulin of patients","authors":"Sylvie Hermouet,&nbsp;Nicolas Mennesson,&nbsp;Sophie Allain-Maillet,&nbsp;Edith Bigot-Corbel,&nbsp;Andri Olafsson,&nbsp;Brynjar Viðarsson,&nbsp;Páll T. Önundarson,&nbsp;Bjarni A. Agnarsson,&nbsp;Margrét Sigurðardóttir,&nbsp;Ingunn Þorsteinsdóttir,&nbsp;Ísleifur Ólafsson,&nbsp;Elías Eyþórsson,&nbsp;Ásbjörn Jónsson,&nbsp;Thorvardur J. Love,&nbsp;Saemundur Rognvaldsson,&nbsp;Einar S. Björnsson,&nbsp;Sigrún Thorsteinsdóttir,&nbsp;Sigurdur Y. Kristinsson","doi":"10.1002/hem3.70053","DOIUrl":"10.1002/hem3.70053","url":null,"abstract":"&lt;p&gt;Antigenic stimulation initiates subsets of plasma cell dyscrasias, including monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM).&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; MGUS and MM are characterized by genetically altered clonal plasma cells that produce large quantities of a single immunoglobulin (Ig), termed “monoclonal Ig (mcIg),” or M-protein. Smoldering multiple myeloma (SMM) is the intermediate stage between asymptomatic MGUS and MM.&lt;span&gt;&lt;sup&gt;2-4&lt;/sup&gt;&lt;/span&gt; In clonal gammopathies, the initial antigenic stimulation can be identified by studying the specificity of recognition of the patient's mcIg. In MGUS and MM, targets of mcIgs (potential initiating events) include infectious pathogens (Epstein-Barr virus [EBV], cytomegalovirus [CMV], Enteroviruses, &lt;i&gt;Helicobacter pylori&lt;/i&gt; [&lt;i&gt;H. pylori&lt;/i&gt;], hepatitis C virus [HCV], hepatitis B virus [HBV]), and self-antigens (glucosylsphingosine [GlcSph]).&lt;span&gt;&lt;sup&gt;1, 5-9&lt;/sup&gt;&lt;/span&gt; Importantly, MGUS or MM linked to CMV infection or anti-GlcSph autoimmunity seem to be benign cases,&lt;span&gt;&lt;sup&gt;1, 5-7&lt;/sup&gt;&lt;/span&gt; and suppression of the antigen target can be envisioned as a potential therapy. Studies of MGUS during Gaucher disease (GD) showed that GlcSph, the immunogenic lipid accumulated in GD, is a frequent target of GD mcIgs.&lt;span&gt;&lt;sup&gt;5, 6&lt;/sup&gt;&lt;/span&gt; Confirming the link between GlcSph and MGUS in GD patients, GlcSph-reducing eliglustat therapy successfully suppressed the plasma clone and mcIg production.&lt;span&gt;&lt;sup&gt;10&lt;/sup&gt;&lt;/span&gt; Viral target antigen reduction also improved response to chemotherapy, as observed with antiviral treatments for MM patients who presented with an HCV- or HBV-specific mcIg, thus likely had HCV- or HBV-initiated disease.&lt;span&gt;&lt;sup&gt;11, 12&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Previous studies have shown that ~15% of sporadic MGUS and MM have a mcIg specific for GlcSph, consistent with chronic autoimmunity, and ~60% MGUS and ~30% MM patients have a mcIg specific for a pathogen, implying that infection initiated the gammopathy.&lt;span&gt;&lt;sup&gt;1, 7-9, 13&lt;/sup&gt;&lt;/span&gt; However, antigen targets of mcIg in SMM remain unknown. Here we analyzed the targets of mcIg of an SMM cohort from the Iceland Screens, Treats or Prevents Multiple Myeloma (iStopMM) consortium&lt;span&gt;&lt;sup&gt;14, 15&lt;/sup&gt;&lt;/span&gt;; patient characteristics according to the target of the mcIg; and the effect of target reduction therapy for SMM patients with &lt;i&gt;H. pylori&lt;/i&gt;-specific mcIg.&lt;/p&gt;&lt;p&gt;We examined 182 individuals (109 males, 73 females) diagnosed with SMM in the iStopMM study during the 2016–2022 period. Serum samples were collected at diagnosis or follow-up visits (every 4–6 months), aliquoted, and frozen (−80°C). McIgs were IgG (&lt;i&gt;n&lt;/i&gt; = 105), IgA (&lt;i&gt;n&lt;/i&gt; = 45), IgM (&lt;i&gt;n&lt;/i&gt; = 1), and light chains (LC) (&lt;i&gt;n&lt;/i&gt; = 26). Five patients (P41, P107, P153, P166, P168) were bi-clonal (had two mcIgs). The male ratio was 60%, and at diagnosis, the median age of patients was 67.5 years, and the median M-protein amo","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 12","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11635023/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142817962","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":"Time-restricted versus standard-duration immunosuppression after allogeneic hematopoietic stem cell transplantation: Results of the prospective randomized HOVON-96 trial","authors":"Annoek E. C. Broers,&nbsp;Ellen Meijer,&nbsp;Bronno van der Holt,&nbsp;Cornelis N. de Jong,&nbsp;Erfan Nur,&nbsp;Geerte L. van Sluis,&nbsp;Goda Choi,&nbsp;Michel van Gelder,&nbsp;Johan A. Maertens,&nbsp;Jürgen Kuball,&nbsp;Dries Deeren,&nbsp;Heleen A. Visser-Wisselaar,&nbsp;Lamberdina A. H. M. Meulendijks,&nbsp;Jan J. Cornelissen,&nbsp;the HOVON Stem Cell Transplantation Working Group","doi":"10.1002/hem3.70040","DOIUrl":"10.1002/hem3.70040","url":null,"abstract":"<p>Cyclosporine A combined with mycophenolate mofetil (CsA/MMF) has become an established regimen for the prevention of graft-versus-host disease (GVHD) following non-myeloablative (NMA) allogeneic hematopoietic stem cell transplantation (alloHSCT). However, the optimal duration of immunosuppression (IS) has not yet been defined and overtreatment is of concern. We hypothesized that time-restricted IS with CsA/MMF would increase the proportion of patients with non-severe GVHD compared to standard-duration IS, thereby resulting in reduction of the relapse rate and improvement of progression-free survival (PFS) and overall survival (OS). In a prospective randomized, multicenter, phase III trial, patients were allocated (1:1) to standard or time-restricted IS. A total of 389 patients were randomized, of whom 369 were transplanted (184 vs. 185 patients). The primary endpoint, the proportion of patients with non-severe GVHD defined as acute GVHD grades I–II without gut involvement or chronic GVHD not requiring systemic treatment within 180 days posttransplant, was 23% after standard-duration IS versus 24% after time-restricted IS (odds ratio: 1.02; 95% confidence interval (CI) 0.63–1.66, <i>p</i> = 0.92). The cumulative incidence of grade III–IV acute GVHD at 6 months posttransplant was not significantly different (14% vs. 18%; <i>p</i> = 0.20). The two-year cumulative incidence of chronic extensive GVHD was 50% versus 46% (<i>p</i> = 0.62). There were no significant differences in the rates of relapse/progression, non-relapse mortality, PFS, OS, and GVHD-free, relapse-free survival. Time-restricted IS with CsA/MMF did not increase the proportion of patients with non-severe GVHD, and secondary outcomes were not different compared to standard-duration IS following NMA-matched alloHSCT.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 12","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11632395/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142813040","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":"Early progression beyond first-line chemoimmunotherapy in follicular lymphoma: Insights from a Fondazione Italiana Linfoma (FIL) study","authors":"Alberto Bavieri,&nbsp;Maria E. Nizzoli,&nbsp;Alessandra Tucci,&nbsp;Vittorio R. Zilioli,&nbsp;Jacopo Olivieri,&nbsp;Benedetta Bianchi,&nbsp;Mansueto G. Rosaria,&nbsp;Ombretta Annibali,&nbsp;Alessia Bari,&nbsp;Gloria M. Casaluci,&nbsp;Michele Cimminiello,&nbsp;Nicola Di Renzo,&nbsp;Federica Cavallo,&nbsp;Vicenzo Pavone,&nbsp;Clara Mannarella,&nbsp;Annalisa Arcari,&nbsp;Maggi Alessandro,&nbsp;Antonella Anastasia,&nbsp;Vittoria Tarantino,&nbsp;Antonino Neri,&nbsp;Massimo Gentile,&nbsp;Fortunato Morabito,&nbsp;Stefano Luminari","doi":"10.1002/hem3.70049","DOIUrl":"10.1002/hem3.70049","url":null,"abstract":"&lt;p&gt;Follicular lymphoma (FL) is the most common indolent B-cell lymphoma.&lt;span&gt;&lt;sup&gt;1, 2&lt;/sup&gt;&lt;/span&gt; While most patients with FL have a truly indolent clinical course with standard therapy (ICT),&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; one out five patients experience early relapse or progression (R/P), leading to notably poor outcomes with a 5-year overall survival (OS) of only 60%.&lt;span&gt;&lt;sup&gt;4, 5&lt;/sup&gt;&lt;/span&gt; These so-called POD24 patients usually show aggressive behavior mainly due to histological transformation (HT) and emergent chemo-resistant disease.&lt;span&gt;&lt;sup&gt;6-13&lt;/sup&gt;&lt;/span&gt; However, not all POD24 patients face unfavorable outcomes, underscoring the need for extensive real-life data to elucidate FL behavior after the first relapse.&lt;span&gt;&lt;sup&gt;14&lt;/sup&gt;&lt;/span&gt; We conducted a retrospective multicenter study to assess the outcomes of a real-world cohort of FL patients at their first relapse. Patients with grade 1 to 3a FL who experienced their first R/P after first-line standard ICT between 2002 and 2017 were eligible. Of note, patients with HT at first relapse were excluded in order to describe a homogeneous FL population. Clinical and laboratory features were documented at diagnosis and the first and second R/P, with optional histological confirmation details of first R/P. The study received approval from ethic committees at each participating institution, and all patients provided informed consent. The primary endpoint was progression-free survival from first relapse (index date; PFS2). The secondary endpoint was survival after the first relapse (SAR). POD24r was defined as disease R/P within 24 months after the start of the first salvage therapy. The endpoint definition is reported in the supplementary material.&lt;/p&gt;&lt;p&gt;The initial cohort included 175 patients, enrolled by 16 centers of Fondazione Italiana Linfomi (FIL), and 155 were confirmed eligible (Supporting Information S1: Figure 1). The key characteristics of patients both at diagnosis and at index date are shown in Table 1. Even if a biopsy was not mandatory, a pathology report consistent with FL at index date was available for 117 cases. Regarding initial therapy, most of the patients were treated with the R-CHOP regimen (98, 63%), and rituximab maintenance was administered in 59 cases. POD24 was documented in 59 patients (38%); 141 patients received a second-line therapy consisting mainly of R-Bendamustine and platinum-based therapy (41; 29%, and 37; 26%, respectively) (Table 1).&lt;/p&gt;&lt;p&gt;After a median follow-up of 48 months from the index date (interquartile range [IQR]: 25–68 months), 64 patients experienced a subsequent relapse or progression with a median PFS2 of 55 months (95% confidence interval [CI], 44–83 months). 4-year PFS2 rates was 55% (95% CI: 46%–63%). In univariate analysis, only male sex, increased beta-2-microglobulin (β2-M) levels at index date, and POD24 predicted lower PFS rates (Supporting Information S1: Table 1 and Supporting Information S1: Figure 2). In multivariate anal","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 12","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11655126/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142854068","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":"High-risk cytogenetic abnormalities in multiple myeloma: PETHEMA-GEM experience","authors":"Veronica González-Calle,&nbsp;Paula Rodriguez-Otero,&nbsp;Maria J. Calasanz,&nbsp;Manuela Guijarro,&nbsp;Joaquin Martínez-López,&nbsp;Laura Rosiñol,&nbsp;Miguel T. Hernández,&nbsp;Ana I. Teruel,&nbsp;Mercedes Gironella,&nbsp;Albert Oriol,&nbsp;Javier de la Rubia,&nbsp;Ana P. González-Rodríguez,&nbsp;Joan Bargay,&nbsp;Felipe de Arriba,&nbsp;Luis Palomera,&nbsp;Marta-Sonia González-Pérez,&nbsp;Anna Sureda,&nbsp;Enrique Ocio,&nbsp;Juan J. Lahuerta,&nbsp;Joan Bladé,&nbsp;Jesus F. San Miguel,&nbsp;Maria V. Mateos,&nbsp;Norma C. Gutiérrez","doi":"10.1002/hem3.70031","DOIUrl":"10.1002/hem3.70031","url":null,"abstract":"<p>This study examines the impact of cytogenetic abnormalities and their co-segregation on the prognosis of newly diagnosed multiple myeloma patients. The analysis included 1304 patients from four different GEM-PETHEMA clinical trials. Genetic alterations, such as t(4;14), t(14;16), del(17p), +1q, and del(1p), were investigated using FISH on CD38 purified plasma cells. The frequency of genetic alterations detected were as follows: del(17p) in 8%, t(4;14) in 12%, t(14;16) in 3%, +1q in 43%, and del(1p) in 8%. The median follow-up was 61 months, and the median progression-free survival (PFS) and overall survival (OS) were 44 months and not reached, respectively. Consistent with previous reports, the presence of t(4;14) was associated with shorter PFS and OS. In our series, the presence of t(14;16) did not impact survival, maybe due to limitations in sample size. Del(17p) was linked to poor prognosis using a cut-off level of ≥20% positive cells, without any impact of higher cut-off in prognosis, except for patients with clonal fraction ≥80% who had a dismal outcome. Cosegregation of cytogenetic abnormalities patients worsened the prognosis in t(4;14) patients but not in patients with del(17p), which retained its adverse prognosis even as a solitary abnormality. Gain(1q) was associated with significantly shorter PFS and OS, while del(1p) affected PFS but not OS. Nevertheless, when co-segregation was eliminated, the detrimental effect of +1q or del(1p) was no longer observed. In conclusion, this study confirms the prognostic significance of high-risk cytogenetic abnormalities in MM and highlights the importance of considering co-occurrence for accurate prognosis assessment.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 12","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11632121/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142812964","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":"Models for the marrow: A comprehensive review of AI-based cell classification methods and malignancy detection in bone marrow aspirate smears","authors":"Tabita Ghete,&nbsp;Farina Kock,&nbsp;Martina Pontones,&nbsp;David Pfrang,&nbsp;Max Westphal,&nbsp;Henning Höfener,&nbsp;Markus Metzler","doi":"10.1002/hem3.70048","DOIUrl":"https://doi.org/10.1002/hem3.70048","url":null,"abstract":"<p>Given the high prevalence of artificial intelligence (AI) research in medicine, the development of deep learning (DL) algorithms based on image recognition, such as the analysis of bone marrow aspirate (BMA) smears, is rapidly increasing in the field of hematology and oncology. The models are trained to identify the optimal regions of the BMA smear for differential cell count and subsequently detect and classify a number of cell types, which can ultimately be utilized for diagnostic purposes. Moreover, AI is capable of identifying genetic mutations phenotypically. This pipeline has the potential to offer an accurate and rapid preliminary analysis of the bone marrow in the clinical routine. However, the intrinsic complexity of hematological diseases presents several challenges for the automatic morphological assessment. To ensure general applicability across multiple medical centers and to deliver high accuracy on prospective clinical data, AI models would require highly heterogeneous training datasets. This review presents a systematic analysis of models for cell classification and detection of hematological malignancies published in the last 5 years (2019–2024). It provides insight into the challenges and opportunities of these DL-assisted tasks.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 12","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70048","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142762548","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":"Cerebral hemodynamics and oxygen metabolism in patients with milder and severe forms of sickle cell disease and thalassemia","authors":"Liza Afzali-Hashemi,&nbsp;Koen P. A. Baas,&nbsp;Anouk Schrantee,&nbsp;Erfan Nur,&nbsp;Chau Vu,&nbsp;Soyoung Choi,&nbsp;Silvie Suriany,&nbsp;John C. Wood,&nbsp;Aart J. Nederveen,&nbsp;Bart J. Biemond","doi":"10.1002/hem3.70022","DOIUrl":"https://doi.org/10.1002/hem3.70022","url":null,"abstract":"<p>Silent cerebral infarcts (SCIs) are present in patients with sickle cell disease (SCD) and thalassemia, but the pathophysiology of SCIs is not fully understood. Previous studies mainly focused on cerebral hemodynamics and oxygen metabolism in patients with severe SCD (HbSS/HbSβ°) but not in milder forms of SCD (HbSC/HbSβ⁺) and thalassemia despite the high prevalence of SCIs in these patients. In this work, we studied the cerebral hemodynamics and oxygen metabolism, and SCI lesion load in 75 severe and 26 mild adult SCD patients, 18 thalassemia patients (as anemic comparison group), and 30 healthy controls before and after a vasodilatory challenge with acetazolamide. Cerebral blood flow was significantly higher in patients with severe SCD and thalassemia compared to patients with mild SCD and controls (<i>p</i> &lt; 0.05). Conversely, oxygen extraction fraction and cerebral metabolic rate of oxygen (CMRO₂) were significantly lower in patients with severe SCD and thalassemia compared to other groups (<i>p</i> &lt; 0.01). In contrast, no difference in SCI volumes was found between mild and severe SCD and thalassemia patients. After acetazolamide administration, oxygen delivery increased less in severe SCD and thalassemia patients compared to other groups (<i>p</i> &lt; 0.01) and CMRO₂ decreased only in severe SCD patients (<i>p</i> &lt; 0.01). Given the reduced CMRO₂ values in severe SCD and thalassemia patients, we conclude that reduced cerebral oxygen consumption in these patient groups is mostly related to anemia. Our data suggest that the pathophysiology of SCIs in patients with milder forms of SCD might be more related to prior episodes of anemia or other sickle cell-related factors.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 12","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70022","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142762105","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":"Interferon gamma-mediated prevention of tumor progression in a mouse model of multiple myeloma","authors":"Zoltán Kellermayer,&nbsp;Sabrin Tahri,&nbsp;Madelon M. E. de Jong,&nbsp;Natalie Papazian,&nbsp;Cathelijne Fokkema,&nbsp;Elodie C. G. Stoetman,&nbsp;Remco Hoogenboezem,&nbsp;Gregory van Beek,&nbsp;Mathijs A. Sanders,&nbsp;Louis Boon,&nbsp;Chelsea Den Hollander,&nbsp;Annemiek Broijl,&nbsp;Pieter Sonneveld,&nbsp;Tom Cupedo","doi":"10.1002/hem3.70047","DOIUrl":"https://doi.org/10.1002/hem3.70047","url":null,"abstract":"<p>Malignant plasma cells in multiple myeloma patients reside in the bone marrow and continuously interact with local immune cells. Progression and therapy response are influenced by this immune environment, highlighting the need for a detailed understanding of endogenous immune responses to malignant plasma cells. Here we used the 5TGM1 murine transfer model of multiple myeloma to dissect early immune responses to myeloma cells. We modeled stable and progressive disease by transferring 5TGM1 murine myeloma cells into C57Bl/6 mice and KaLwRij mice, respectively. We used flow cytometry and single-cell and bulk transcriptomic analyses to characterize differential immune responses in stable and progressive disease. Transfer of 5TGM1 cells in C57Bl/6 mice led to stable disease with low tumor burden in a subset of animals. Stable disease was associated with sustained activation and expansion of NK cells, ILC1, and CD8⁺ T cells, a response that was lost upon disease progression. Single-cell RNA-sequencing of immune cells and bulk RNA sequencing of immune and mesenchymal stromal cells implicated the activation of interferon responses as a central immune pathway during stable disease. Experimentally, neutralization of IFNγ significantly increased myeloma development and progression in C57Bl/6 mice, testifying to the importance of this pathway in early disease control. In conclusion, we provide a framework for studying immune responses to multiple myeloma progression in immunocompetent and genetically modifiable mice and highlight the importance of bone marrow immunity in tumor control.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 12","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70047","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142762104","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":"Dual specific STAT3/5 degraders effectively block acute myeloid leukemia and natural killer/T cell lymphoma","authors":"Daniel Pölöske,&nbsp;Helena Sorger,&nbsp;Anna Schönbichler,&nbsp;Elvin D. de Araujo,&nbsp;Heidi A. Neubauer,&nbsp;Anna Orlova,&nbsp;Sanna H. Timonen,&nbsp;Diaaeldin I. Abdallah,&nbsp;Aleksandr Ianevski,&nbsp;Heikki Kuusanmäki,&nbsp;Marta Surbek,&nbsp;Elisabeth Heyes,&nbsp;Thomas Eder,&nbsp;Christina Wagner,&nbsp;Tobias Suske,&nbsp;Martin L. Metzelder,&nbsp;Michael Bergmann,&nbsp;Maik Dahlhoff,&nbsp;Florian Grebien,&nbsp;Roman Fleck,&nbsp;Christine Pirker,&nbsp;Walter Berger,&nbsp;Emir Hadzijusufovic,&nbsp;Wolfgang R. Sperr,&nbsp;Lukas Kenner,&nbsp;Peter Valent,&nbsp;Tero Aittokallio,&nbsp;Marco Herling,&nbsp;Satu Mustjoki,&nbsp;Patrick T. Gunning,&nbsp;Richard Moriggl","doi":"10.1002/hem3.70001","DOIUrl":"https://doi.org/10.1002/hem3.70001","url":null,"abstract":"<p>The transcription factors STAT3, STAT5A, and STAT5B steer hematopoiesis and immunity, but their enhanced expression and activation promote acute myeloid leukemia (AML) or natural killer/T cell lymphoma (NKCL). Current therapeutic strategies focus on blocking upstream tyrosine kinases to inhibit STAT3/5, but these kinase blockers are not selective against STAT3/5 activation and frequent resistance causes relapse, emphasizing the need for targeted drugs. We evaluated the efficacy of JPX-0700 and JPX-0750 as dual STAT3/5 binding inhibitors promoting protein degradation. JPX-0700/−0750 decreased the mRNA and protein levels of STAT3/5 targets involved in cancer survival, metabolism, and cell cycle progression, exhibiting nanomolar to low micromolar efficacy. They induced cell death and growth arrest in both AML/NKCL cell lines and primary AML patient blasts. We found that both AML/NKCL cells hijack STAT3/5 signaling through either upstream activating mutations in kinases, activating mutations in STAT3, mutational loss of negative STAT regulators, or genetic gains in anti-apoptotic, pro-proliferative, or epigenetic-modifying STAT3/5 targets. This emphasizes a vicious cycle for proliferation and survival through STAT3/5. Both JPX-0700/−0750 treatment reduced leukemic cell growth in human AML or NKCL xenograft mouse models significantly, being well tolerated by mice. Synergistic cell death was induced upon combinatorial use with approved chemotherapeutics in AML/NKCL cells.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 12","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70001","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142749325","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}