HemaSphere最新文献

{"title":"Combined inhibition of CTPS1 and ATR is a metabolic vulnerability in p53-deficient myeloma cells","authors":"Romane Durand,&nbsp;Céline Bellanger,&nbsp;Géraldine Descamps,&nbsp;Christelle Dousset,&nbsp;Sophie Maïga,&nbsp;Jennifer Derrien,&nbsp;Laura Thirouard,&nbsp;Louise Bouard,&nbsp;Hélène Asnagli,&nbsp;Philip Beer,&nbsp;Andrew Parker,&nbsp;Patricia Gomez-Bougie,&nbsp;Marie-Claire Devilder,&nbsp;Philippe Moreau,&nbsp;Cyrille Touzeau,&nbsp;Agnès Moreau-Aubry,&nbsp;David Chiron,&nbsp;Catherine Pellat-Deceunynck","doi":"10.1002/hem3.70016","DOIUrl":"10.1002/hem3.70016","url":null,"abstract":"<p>In multiple myeloma, as in B-cell malignancies, mono- and especially bi-allelic <i>TP53</i> gene inactivation is a high-risk factor for treatment resistance, and there are currently no therapies specifically targeting p53 deficiency. In this study, we evaluated if the loss of cell cycle control in p53-deficient myeloma cells would confer a metabolically actionable vulnerability. We show that CTP synthase 1 (<i>CTPS1</i>), which encodes a CTP synthesis rate-limiting enzyme essential for DNA and RNA synthesis in lymphoid cells, is overexpressed in samples from myeloma patients displaying a high proliferation rate (high <i>MKI67</i> expression) or a low p53 score (synonymous with <i>TP53</i> deletion and/or mutation). This overexpression of <i>CTPS1</i> was associated with reduced survival in two cohorts. Using scRNA-seq analysis in 24 patient samples, we further demonstrate that myeloma cells in the S or G2/M phase display high <i>CTPS1</i> expression. Pharmacological inhibition of CTPS1 by STP-B induced cell cycle arrest in early S phase in isogenic NCI-H929 or XG7 <i>TP53</i>^+/+, <i>TP53</i>^−/−, and <i>TP53</i>^R175H/R175H cells and in a <i>TP53</i>^−/R123STOP patient sample. The functional annotation of transcriptional changes in 10 STP-B-treated myeloma cell lines revealed a decrease in protein translation and confirmed the blockade of cells into the S phase. The pharmacological inhibition of ATR, which governs the intrinsic S/G2 checkpoint, in STP-B-induced S-phase arrested cells synergistically induced cell death in <i>TP53</i>^+/+, <i>TP53</i>^−/−, and <i>TP53</i>^R175H/R175H isogenic cell lines (Bliss score &gt;15). This combination induced replicative stress and caspase-mediated cell death and was highly effective in resistant/refractory patient samples with <i>TP53</i> deletion and/or mutation and in <i>TP53</i>^−/− NCI-H929 xenografted NOD-scid IL2Rgamma mice. Our in vitro, ex vivo, and in vivo data provide the rationale for combined CTPS1 and ATR inhibition for the treatment of p53-deficient patients.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 10","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11460984/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142390133","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":"The changing influence of neighborhood socioeconomic status on long-term survival in diffuse large B-cell lymphoma patients: A German metropolitan case-control study spanning over three decades","authors":"Susanne Ghandili,&nbsp;Judith Dierlamm,&nbsp;Carsten Bokemeyer,&nbsp;Henrik Kusche,&nbsp;Frederik Peters","doi":"10.1002/hem3.70011","DOIUrl":"10.1002/hem3.70011","url":null,"abstract":"&lt;p&gt;An increasing body of evidence suggests that area-based socioeconomic status (SES) in addition to patient and disease characteristics might be viewed as a relevant prognostic factor for long-term survival in diffuse large B-cell lymphoma (DLBCL) patients.&lt;span&gt;&lt;sup&gt;1-6&lt;/sup&gt;&lt;/span&gt; Possible explanations focused on barriers to care due to lack of adequate health insurance resulting in delayed or inadequate care&lt;span&gt;&lt;sup&gt;1, 6&lt;/sup&gt;&lt;/span&gt; while there is also evidence that large-scale implementation of CD20-directed immunochemotherapy in the standard of care considerably affected DLBCL-specific survival at the population level.&lt;span&gt;&lt;sup&gt;7&lt;/sup&gt;&lt;/span&gt; Here, we investigate the extent to which the introduction of rituximab-based immunochemotherapy has affected socioeconomic status (SES) disparities in all-cause overall survival (OS). This retrospective, case-control study conducts a population-based analysis in a German metropolitan area over a period of 32 years, encompassing the time before and after the introduction of up-front CD20-directed immunochemotherapy within a universal healthcare system.&lt;/p&gt;&lt;p&gt;DLBCL cases were reported to the Hamburg Cancer Registry between January 1, 1990 and December 31, 2022, as the first occurrence of a primary diagnosis “C83.3” according to the International Statistical Classification of Diseases, German Modification (ICD-10-GM in combination with morphology “9680” or “9684” of the International Classification of Diseases for Oncology, 3rd Edition (ICD-O-3). Patients under 18 years, without a residency in Hamburg, with an incomplete record (e.g., information only from pathology report or death certificate), with a DLBCL location at the central nervous system (ICD-O-3 “C70,” “C71,” or “C72”), a follow-up duration of less than 3 months, or incomplete information regarding sex or SES were excluded. For assessing the impact of the introduction of modern immunochemotherapy in 2003, the sample was divided into two sub-cohorts (controls diagnosed between 1990 and 2003 and thus defining the pre-rituximab era and cases diagnosed between 2004 and 2022 defining the rituximab era). Patients with a primary diagnosis of T-cell lymphoma (ICD-10-GM coding “C84.4,” “C84.6,” “C84.7,” “C86.5”) in 1990–2022 were used as negative controls, as these patients did not benefit from the breakthrough in modern immunochemotherapy as DLBCL patient did. The SES index, hereinafter “SES,” refers to the deprivation score “Sozialindex” for the City of Hamburg, which is defined for each of the 103 urban districts in Hamburg by the Social Welfare Authority of the Free and Hanseatic City of Hamburg and calculated in 2011 and 2020. The index is based on statistics related to household income, social housing, house/apartment sizes per head, and welfare reception as an indirect proxy of income.&lt;span&gt;&lt;sup&gt;8&lt;/sup&gt;&lt;/span&gt; Based on the quintiles of the index score the SES was grouped into low, middle, and high and thereafter assigned to patients based on ","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 10","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11459230/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142390138","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":"Correction to “Single-cell RNA sequencing of pediatric Hodgkin lymphoma to study the inhibition of T cell subtypes”","authors":"","doi":"10.1002/hem3.70023","DOIUrl":"10.1002/hem3.70023","url":null,"abstract":"<p>de Kanter J, Steemers A, González D, et al. Single-cell RNA sequencing of pediatric Hodgkin lymphoma to study the inhibition of T cell subtypes. <i>HemaSphere</i>. 2024;8:e149.</p><p>In the author listing of the manuscript, the first name of an author was incorrectly listed as Daniel Montiel Gonzalez. The correct name is Diego Montiel González.</p><p>The original publication has been corrected. We apologize for this error.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 10","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11456745/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142390134","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":"Testicular large B-cell lymphoma is genetically similar to PCNSL and distinct from nodal DLBCL","authors":"Alfredo Rivas-Delgado,&nbsp;Cristina López,&nbsp;Guillem Clot,&nbsp;Ferran Nadeu,&nbsp;Marta Grau,&nbsp;Gerard Frigola,&nbsp;Jan Bosch-Schips,&nbsp;Josefine Radke,&nbsp;Naveed Ishaque,&nbsp;Miguel Alcoceba,&nbsp;Gustavo Tapia,&nbsp;Luis Luizaga,&nbsp;Carmen Barcena,&nbsp;Nicholas Kelleher,&nbsp;Neus Villamor,&nbsp;Tycho Baumann,&nbsp;Ana Muntañola,&nbsp;Juan M. Sancho-Cia,&nbsp;Alejandro M. García-Sancho,&nbsp;Eva Gonzalez-Barca,&nbsp;Estella Matutes,&nbsp;Jordi A. Brito,&nbsp;Kennosuke Karube,&nbsp;Itziar Salaverria,&nbsp;Anna Enjuanes,&nbsp;Stefan Wiemann,&nbsp;Frank L. Heppner,&nbsp;Reiner Siebert,&nbsp;Fina Climent,&nbsp;Elías Campo,&nbsp;Eva Giné,&nbsp;Armando López-Guillermo,&nbsp;Silvia Beà","doi":"10.1002/hem3.70024","DOIUrl":"10.1002/hem3.70024","url":null,"abstract":"<p>Testicular large B-cell lymphoma (TLBCL) is an infrequent and aggressive lymphoma arising in an immune-privileged site and has recently been recognized as a distinct entity from diffuse large B-cell lymphoma (DLBCL). We describe the genetic features of TLBCL and compare them with published series of nodal DLBCL and primary large B-cell lymphomas of the CNS (PCNSL). We collected 61 patients with TLBCL. We performed targeted next-generation sequencing, copy number arrays, and fluorescent <i>in situ</i> hybridization to assess chromosomal rearrangements in 40 cases with available material. Seventy percent of the cases showed localized stages. <i>BCL6</i> rearrangements were detected in 36% of cases, and no concomitant <i>BCL2</i> and <i>MYC</i> rearrangements were found. TLBCL had fewer copy number alterations (<i>p </i>&lt; 0.04) but more somatic variants (<i>p </i>&lt; 0.02) than nodal DLBCL and had more frequent 18q21.32-q23 (<i>BCL2</i>) gains and 6q and 9p21.3 (<i>CDKN2A/B</i>) deletions. <i>PIM1</i>, <i>MYD88</i>^<i>L265P</i>, <i>CD79B</i>, <i>TBL1XR1</i>, <i>MEF2B</i>, <i>CIITA</i>, <i>EP300,</i> and <i>ETV6</i> mutations were more frequent in TLBCL, and <i>BCL10</i> mutations in nodal DLBCL. There were no major genetic differences between TLBCL and PCNSL. Localized or disseminated TLBCL displayed similar genomic profiles. Using LymphGen, the majority of cases were classified as MCD. However, we observed a subgroup of patients classified as BN2, both in localized and disseminated TLBCL, suggesting a degree of genetic heterogeneity in the TLBCL genetic profile. TLBCL has a distinctive genetic profile similar to PCNSL, supporting its recognition as a separate entity from DLBCL and might provide information to devise targeted therapeutic approaches.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 10","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11456803/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142390137","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":"Safe and potent anti-CD19 CAR T-cells with shRNA-IL-6 gene silencing element in patients with refractory or relapsed B-cell acute lymphoblastic leukemia","authors":"Jin-Feng Ma,&nbsp;Jia-Wei Yan,&nbsp;Mei-Jing Liu,&nbsp;Chun-Long Yan,&nbsp;Xiao-Wen Tang,&nbsp;Hui-Ying Qiu,&nbsp;Miao Miao,&nbsp;Yue Han,&nbsp;Li-Min Li,&nbsp;Li-Qing Kang,&nbsp;Nan Xu,&nbsp;Zhou Yu,&nbsp;Jing-Wen Tan,&nbsp;Hong-Jia Zhu,&nbsp;Xu Jia,&nbsp;Zhi-Zhi Zhang,&nbsp;Miao Wang,&nbsp;Hai-Ping Dai,&nbsp;Lei Yu,&nbsp;Sheng-Li Xue,&nbsp;De-Pei Wu,&nbsp;Wen-Jie Gong","doi":"10.1002/hem3.70007","DOIUrl":"10.1002/hem3.70007","url":null,"abstract":"<p>Severe cytokine release syndrome (sCRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) have limited the widespread use of chimeric antigen receptor T (CAR T)-cell therapy. We designed a novel anti-CD19 CAR (ssCART-19) with a small hairpin RNA (shRNA) element to silence the interleukin-6 (IL-6) gene, hypothesizing it could reduce sCRS and ICANS by alleviating monocyte activation and proinflammatory cytokine release. In a post hoc analysis of two clinical trials, we compared ssCART-19 with common CAR T-cells (cCART-19) in relapsed/refractory B-cell acute lymphoblastic leukemia (r/r B-ALL). Among 87 patients, 47 received ssCART-19 and 40 received cCART-19. Grade ≥3 CRS occurred in 14.89% (7/47) of the ssCART-19 group versus 37.5% (15/40) in the cCART-19 group (<i>p</i> = 0.036). ICANS occurred in 4.26% (2/47) of the ssCART-19 group (all grade 1) compared to 15% (2/40) of the cCART-19 group. Patients in the ssCART-19 group showed comparable rates of treatment response (calculated with rates of complete remission and incomplete hematological recovery) were 91.49% (43/47) for ssCART-19 and 85% (34/40) for cCART-19 (<i>p</i> = 0.999). With a median follow-up of 21.9 months, cumulative nonrelapse mortality was 10.4% for ssCART-19 and 13.6% for cCART-19 (<i>p</i> = 0.33). Median overall survival was 37.17 months for ssCART-19 and 32.93 months for cCART-19 (<i>p</i> = 0.40). Median progression-free survival was 24.17 months for ssCART-19 and 9.33 months for cCART-19 (<i>p</i> = 0.23). These data support the safety and efficacy of ssCART-19 for r/r B-ALL, suggesting its potential as a promising therapy.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 10","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11456753/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142390136","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":"Activating mutations remodel the chromatin accessibility landscape to drive distinct regulatory networks in KMT2A-rearranged acute leukemia","authors":"Qirui Zhang,&nbsp;Ton Falqués-Costa,&nbsp;Mattias Pilheden,&nbsp;Helena Sturesson,&nbsp;Tina Ovlund,&nbsp;Vendela Rissler,&nbsp;Anders Castor,&nbsp;Hanne V. H. Marquart,&nbsp;Birgitte Lausen,&nbsp;Thoas Fioretos,&nbsp;Axel Hyrenius-Wittsten,&nbsp;Anna K. Hagström-Andersson","doi":"10.1002/hem3.70006","DOIUrl":"https://doi.org/10.1002/hem3.70006","url":null,"abstract":"<p>Activating <i>FLT3</i> and <i>RAS</i> mutations commonly occur in leukemia with <i>KMT2A</i>-gene rearrangements (<i>KMT2A</i>-r). However, how these mutations cooperate with the <i>KMT2A</i>-r to remodel the epigenetic landscape is unknown. Using a retroviral acute myeloid leukemia (AML) mouse model driven by <i>KMT2A::MLLT3</i>, we show that <i>FLT3</i>^<i>ITD</i>, <i>FLT3</i>^<i>N676K</i>, and <i>NRAS</i>^<i>G12D</i> remodeled the chromatin accessibility landscape and associated transcriptional networks. Although the activating mutations shared a common core of chromatin changes, each mutation exhibits unique profiles with most opened peaks associating with enhancers in intronic or intergenic regions. Specifically, <i>FLT3</i>^<i>N676K</i> and <i>NRAS</i>^<i>G12D</i> rewired similar chromatin and transcriptional networks, distinct from those mediated by <i>FLT3</i>^<i>ITD</i>. Motif analysis uncovered a role for the AP-1 family of transcription factors in <i>KMT2A::MLLT3</i> leukemia with <i>FLT3</i>^<i>N676K</i> and <i>NRAS</i>^<i>G12D</i>, whereas Runx1 and Stat5a/Stat5b were active in the presence of <i>FLT3</i>^<i>ITD</i>. Furthermore, transcriptional programs linked to immune cell regulation were activated in <i>KMT2A</i>-r AML expressing <i>NRAS</i>^<i>G12D</i> or <i>FLT3</i>^<i>N676K</i>, and the expression of NKG2D-ligands on <i>KMT2A</i>-r cells rendered them sensitive to CAR T cell-mediated killing. Human <i>KMT2A</i>-r AML cells could be pharmacologically sensitized to NKG2D-CAR T cells by treatment with the histone deacetylase inhibitor LBH589 (panobinostat) which caused upregulation of NKG2D-ligand levels. Co-treatment with LBH589 and NKG2D-CAR T cells enabled robust AML cell killing, and the strongest effect was observed for cells expressing <i>NRAS</i>^<i>G12D</i>. Finally, the results were validated and extended to acute leukemia in infancy. Combined, activating mutations induced mutation-specific changes in the epigenetic landscape, leading to changes in transcriptional programs orchestrated by specific transcription factor networks.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 9","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70006","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142324559","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":"NUP98 oncofusions in myeloid malignancies: An update on molecular mechanisms and therapeutic opportunities","authors":"Milad Rasouli,&nbsp;Selina Troester,&nbsp;Florian Grebien,&nbsp;Bianca F. Goemans,&nbsp;C. Michel Zwaan,&nbsp;Olaf Heidenreich","doi":"10.1002/hem3.70013","DOIUrl":"https://doi.org/10.1002/hem3.70013","url":null,"abstract":"<p>Acute myeloid leukemia (AML) is an aggressive hematological malignancy with a heterogeneous molecular landscape. In the pediatric context, the <i>NUP98</i> gene is a frequent target of chromosomal rearrangements that are linked to poor prognosis and unfavorable treatment outcomes in different AML subtypes. The translocations fuse <i>NUP98</i> to a diverse array of partner genes, resulting in fusion proteins with novel functions. NUP98 fusion oncoproteins induce aberrant biomolecular condensation, abnormal gene expression programs, and re-wired protein interactions which ultimately cause alterations in the cell cycle and changes in cellular structures, all of which contribute to leukemia development. The extent of these effects is steered by the functional domains of the fusion partners and the influence of concomitant somatic mutations. In this review, we discuss the complex characteristics of NUP98 fusion proteins and potential novel therapeutic approaches for NUP98 fusion-driven AML.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 9","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70013","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142320910","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":"Comprehensive sequential genetic analysis delineating frequency, patterns, and prognostic impact of genomic dynamics in a real-world cohort of patients with lower-risk MDS","authors":"Paolo Mazzeo,&nbsp;Christina Ganster,&nbsp;John Wiedenhöft,&nbsp;Katayoon Shirneshan,&nbsp;Katharina Rittscher,&nbsp;Elzbieta B. Brzuszkiewicz,&nbsp;Doris Steinemann,&nbsp;Maximilian Schieck,&nbsp;Catharina Müller-Thomas,&nbsp;Hannes Treiber,&nbsp;Friederike Braulke,&nbsp;Ulrich Germing,&nbsp;Katja Sockel,&nbsp;Ekaterina Balaian,&nbsp;Julie Schanz,&nbsp;Uwe Platzbecker,&nbsp;Katharina S. Götze,&nbsp;Detlef Haase","doi":"10.1002/hem3.70014","DOIUrl":"10.1002/hem3.70014","url":null,"abstract":"<p>The acquisition of subsequent genetic lesions (clonal evolution, CE) and/or the expansion of existing clones (CEXP) contributes to clonal dynamics (CD) in myelodysplastic syndromes (MDS). Although CD plays an important role in high-risk patients in disease progression and transformation into acute myeloid leukemia (AML), knowledge about CD in lower-risk MDS (LR-MDS) patients is limited due to lack of robust longitudinal data considering the long clinically stable courses of the disease. In this retrospective analysis, we delineate the frequency and the prognostic impact of CD in an unselected real-world cohort of LR-MDS patients. We screened 68 patients with a median follow-up of 40.5 months and a median of 7.5 (range: 2–22) timepoints for CE and CEXP detected by chromosomal banding analysis, fluorescence in situ hybridization, sequencing, and molecular karyotyping. In 30/68 patients, 47 CE events and a CD rate of 1 event per 4 years were documented. Of note, patients with at least 1 CE event had an increased probability for subsequent treatment. Unexpectedly, CE did not correlate with inferior outcomes, which could be reasonably explained by CD detection triggering the subsequent start of a disease-modifying therapy.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 9","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11417473/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142307652","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":"Characterization of myeloid-derived suppressor cells in the peripheral blood and bone marrow of patients with chronic idiopathic neutropenia","authors":"Nikoleta Bizymi,&nbsp;Athina Damianaki,&nbsp;Nikoletta Aresti,&nbsp;Anastasios Karasachinidis,&nbsp;Zacharenia Vlata,&nbsp;Matthieu Lavigne,&nbsp;Emmanuel Dialynas,&nbsp;Niki Gounalaki,&nbsp;Irene Stratidaki,&nbsp;Grigorios Tsaknakis,&nbsp;Aristea Batsali,&nbsp;Irene Mavroudi,&nbsp;Maria Velegraki,&nbsp;Ioannis Sperelakis,&nbsp;Charalampos Pontikoglou,&nbsp;Panayotis Verginis,&nbsp;Helen A. Papadaki","doi":"10.1002/hem3.70005","DOIUrl":"10.1002/hem3.70005","url":null,"abstract":"&lt;p&gt;Chronic idiopathic neutropenia (CIN) is characterized by the persistent and unexplained reduction of peripheral blood (PB) absolute neutrophil counts (ANCs).&lt;span&gt;&lt;sup&gt;1, 2&lt;/sup&gt;&lt;/span&gt; The pathogenesis of CIN has been associated with increased apoptosis of the granulocytic progenitor cells due to an inflammatory bone marrow (BM) microenvironment consisting of activated T lymphocytes, proinflammatory monocytes, and proapoptotic cytokines.&lt;span&gt;&lt;sup&gt;3-5&lt;/sup&gt;&lt;/span&gt; The myeloid-derived suppressor cells (MDSCs) are immature myeloid cells, deviating from the standard differentiation pathway during emergency myelopoiesis, that display immunomodulatory properties mainly by suppressing T-cell responses. They are recognized by the immunophenotype CD11b&lt;sup&gt;+&lt;/sup&gt;CD33&lt;sup&gt;+&lt;/sup&gt;HLA-DR&lt;sup&gt;–/low&lt;/sup&gt; and further characterized as CD14&lt;sup&gt;+&lt;/sup&gt; (monocytic, M-MDSCs) and CD15&lt;sup&gt;+&lt;/sup&gt; (polymorphonuclear, PMN-MDSCs) subpopulations.&lt;span&gt;&lt;sup&gt;6-13&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;In the present study, we explore, for the first time, the possible involvement of MDSCs in the pathophysiology of CIN by investigating their number, functional characteristics, and transcriptome profile in a group of patients (&lt;i&gt;n&lt;/i&gt; = 102) and age- and sex-matched healthy controls (&lt;i&gt;n&lt;/i&gt; = 77). The patients fulfilled the previously described diagnostic criteria for CIN (File S1).&lt;span&gt;&lt;sup&gt;2, 14, 15&lt;/sup&gt;&lt;/span&gt; Sixteen patients had clonal hematopoiesis identified by next-generation sequencing analysis of 40 recurrently mutated myeloid genes.&lt;span&gt;&lt;sup&gt;15&lt;/sup&gt;&lt;/span&gt; The clinical and laboratory data of the patients are presented in Supporting Information S1: Tables 1 and 2. The study was approved by the Institutional Review Board of the University Hospital of Heraklion and informed consent was obtained from all subjects.&lt;/p&gt;&lt;p&gt;MDSC subsets were quantitated and sorted by flow cytometry in the PB mononuclear cell (PBMC) and BM mononuclear cell (BMMC) fractions according to the recommended protocol.&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; The gating strategies for MDSC quantification and sorting are presented in Figure 1A,B respectively. The methodology of the T-cell suppression assay to evaluate the function of MDSCs was performed according to the recommended standards (File S1).&lt;span&gt;&lt;sup&gt;6, 18, 19&lt;/sup&gt;&lt;/span&gt; In brief, the suppression of normal T cells was demonstrated in a heterologous system including co-culture of immunomagnetically sorted carboxy-fluorescein succinimidyl ester (CFSE)-stained T cells with PMN-MDSCs or M-MDSCs (Figure 1C) and an autologous system including cultures of CFSE-stained PBMCs versus CD33-immunomagnetically depleted PBMCs (Figure 1D). To identify the biochemical and molecular parameters associated with MDSC characterization,&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; we performed transcriptional profiling of MDSCs from patients (&lt;i&gt;n&lt;/i&gt; = 6) and healthy controls (&lt;i&gt;n&lt;/i&gt; = 5) using RNA sequencing (File S1 and Supporting Information S1: Table 3). The data were analyzed using the Gra","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 9","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11417472/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142307651","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":"Therapeutic strategies and treatment sequencing in patients with chronic lymphocytic leukemia: An international study of ERIC, the European Research Initiative on CLL","authors":"Thomas Chatzikonstantinou,&nbsp;Lydia Scarfò,&nbsp;Eva Minga,&nbsp;Georgios Karakatsoulis,&nbsp;Dimitra Chamou,&nbsp;Jana Kotaskova,&nbsp;Gloria Iacoboni,&nbsp;Christos Demosthenous,&nbsp;Elisa Albi,&nbsp;Miguel Alcoceba,&nbsp;Salem Al-Shemari,&nbsp;Thérèse Aurran-Schleinitz,&nbsp;Francesca Bacchiarri,&nbsp;Sofia Chatzileontiadou,&nbsp;Rosa Collado,&nbsp;Zadie Davis,&nbsp;Marcos Daniel de Deus Santos,&nbsp;Maria Dimou,&nbsp;Elena Dmitrieva,&nbsp;David Donaldson,&nbsp;Gimena Dos Santos,&nbsp;Barbara Dreta,&nbsp;Maria Efstathopoulou,&nbsp;Shaimaa El-Ashwah,&nbsp;Alicia Enrico,&nbsp;Andrzej Frygier,&nbsp;Sara Galimberti,&nbsp;Andrea Galitzia,&nbsp;Eva Gimeno,&nbsp;Valerio Guarente,&nbsp;Romain Guieze,&nbsp;Sean Harrop,&nbsp;Eleftheria Hatzimichael,&nbsp;Yair Herishanu,&nbsp;José-Ángel Hernández-Rivas,&nbsp;Ozren Jaksic,&nbsp;Elżbieta Kalicińska,&nbsp;Kamel Laribi,&nbsp;Volkan Karakus,&nbsp;Arnon P. Kater,&nbsp;Bonnie Kho,&nbsp;Maria Kislova,&nbsp;Εliana Konstantinou,&nbsp;Maya Koren-Michowitz,&nbsp;Ioannis Kotsianidis,&nbsp;Zuzana Kubova,&nbsp;Jorge Labrador,&nbsp;Deepesh Lad,&nbsp;Luca Laurenti,&nbsp;Thomas Longval,&nbsp;Alberto Lopez-Garcia,&nbsp;Juan Marquet,&nbsp;Stanislava Maslejova,&nbsp;Carlota Mayor-Bastida,&nbsp;Biljana Mihaljevic,&nbsp;Ivana Milosevic,&nbsp;Fatima Miras,&nbsp;Riccardo Moia,&nbsp;Marta Morawska,&nbsp;Uttam K. Nath,&nbsp;Almudena Navarro-Bailón,&nbsp;Jacopo Olivieri,&nbsp;Irina Panovska-Stavridis,&nbsp;Maria Papaioannou,&nbsp;Cheyenne Pierie,&nbsp;Anna Puiggros,&nbsp;Gianluigi Reda,&nbsp;Gian M. Rigolin,&nbsp;Rosa Ruchlemer,&nbsp;Mattia Schipani,&nbsp;Annett Schiwitza,&nbsp;Yandong Shen,&nbsp;Tereza Shokralla,&nbsp;Martin Simkovic,&nbsp;Svetlana Smirnova,&nbsp;Dina S. A. Soliman,&nbsp;Stephan Stilgenbauer,&nbsp;Tamar Tadmor,&nbsp;Kristina Tomic,&nbsp;Eric Tse,&nbsp;Theodoros Vassilakopoulos,&nbsp;Andrea Visentin,&nbsp;Candida Vitale,&nbsp;George Vrachiolias,&nbsp;Vojin Vukovic,&nbsp;Renata Walewska,&nbsp;Zhenshu Xu,&nbsp;Munci Yagci,&nbsp;Lucrecia Yañez,&nbsp;Mohamed Yassin,&nbsp;Jana Zuchnicka,&nbsp;David Oscier,&nbsp;Alessandro Gozzetti,&nbsp;Panagiotis Panagiotidis,&nbsp;Francesc Bosch,&nbsp;Paolo Sportoletti,&nbsp;Blanca Espinet,&nbsp;Gerassimos A. Pangalis,&nbsp;Viola M. Popov,&nbsp;Stephen Mulligan,&nbsp;Maria Angelopoulou,&nbsp;Fatih Demirkan,&nbsp;Tomas Papajík,&nbsp;Bella Biderman,&nbsp;Roberta Murru,&nbsp;Marta Coscia,&nbsp;Constantine Tam,&nbsp;Antonio Cuneo,&nbsp;Gianluca Gaidano,&nbsp;Rainer Claus,&nbsp;Niki Stavroyianni,&nbsp;Livio Trentin,&nbsp;Darko Antic,&nbsp;Lukas Smolej,&nbsp;Olga B. Kalashnikova,&nbsp;Mark Catherwood,&nbsp;Martin Spacek,&nbsp;Sarka Pospisilova,&nbsp;Michael Doubek,&nbsp;Eugene Nikitin,&nbsp;Anastasia Chatzidimitriou,&nbsp;Paolo Ghia,&nbsp;Kostas Stamatopoulos","doi":"10.1002/hem3.70004","DOIUrl":"https://doi.org/10.1002/hem3.70004","url":null,"abstract":"&lt;p&gt;Novel small molecule inhibitors have revolutionized the treatment of chronic lymphocytic leukemia (CLL). Indeed, BTK (BTKi) and BCL2 inhibitors (BCL2i) alone or in combination with each other or other compounds have proven superior to chemoimmunotherapy (CIT) in both the frontline and the relapsed/refractory (R/R) setting.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;ERIC, the European Research Initiative on CLL, conducted this international multicenter retrospective study focused on the era of CIT, aiming to (i) reveal the treatment patterns in the “real world” and (ii) assess the outcomes of patients who received frontline treatment between 2000 and 2016. Overall, 7382 patients with CLL (7134, 96.6%) or SLL (248, 3.4%) from 76 centers in 25 countries in five continents were included. The median age at diagnosis was 64 (interquartile range [IQR]: 56–71) years and the median age at first treatment was 66 (IQR: 58–74) years. The median follow-up was 7.33 (IQR: 4.56–10.81) years from diagnosis and 5.27 (IQR: 3.04–7.99) from first treatment. The vast majority of patients (6873/7134, 93.2%) received at least one line of chemotherapy or CIT; only 197/7134 (2.7%) received exclusively novel agents. Baseline characteristics and disease-specific biomarkers are listed in Supporting Information Material.&lt;/p&gt;&lt;p&gt;The most common first-line regimen was FCR (2609, 35.3%), mostly in young patients (median age at first treatment: 60 years, IQR: 54–66), followed by chlorambucil monotherapy (1293, 17.5%), mostly in older patients (median age at first treatment: 74 years, IQR: 65–80). BTKis as first-line treatment were used in 149/7134 (2%) patients who either participated in clinical trials and/or had &lt;i&gt;TP53&lt;/i&gt; aberrations; 20/7134 (0.3%) received frontline venetoclax-based regimens, all in the context of clinical trials (Figure 1). Detailed outcomes for the most common frontline regimens are provided in Supporting Information Material.&lt;/p&gt;&lt;p&gt;BTKis were the most common type of R/R treatment (1581/8145, 19.4%). Reflecting the approval of novel agents for patients with R/R CLL, the use of all types of chemotherapy and CIT decreased after 2014, except bendamustine plus rituximab (Figure 2).&lt;/p&gt;&lt;p&gt;There were 387 patients with an early (&lt;24 months) need for second-line treatment after 2016: 203/387 (52.4%) received chemotherapy and CIT, 147/387 (38%) novel agents (108/387 [27.9%] BTKi, 24/387 [6.2%] PI3Ki, and 15/387 [3.9%] venetoclax-based treatments), and 37/387 (9.6%) other treatments (Figure 2 &amp; File S1). ORR and discontinuation rates due to progression of patients treated with novel agents are given in the File S1.&lt;/p&gt;&lt;p&gt;Among patients treated with BTKi with or without anti-CD20 monoclonal antibodies (Mab), 55/567 (9.7%) discontinued treatment due to toxicity in second and 120/1014 (11.8%) in later lines. The median time to discontinuation was 5 months (95% confidence interval [CI]: 3.7–12.5) for patients treated in second line and 14 months (95% CI: 8–20.9) for patie","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 9","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70004","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142244977","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}