HemaSphere最新文献

{"title":"Transcriptional profiling directs the classification of acute leukemias of ambiguous lineage into AML, B-ALL, or T-ALL","authors":"Roger Mulet-Lazaro,&nbsp;Anikó Sijs-Szabó,&nbsp;Remco M. Hoogenboezem,&nbsp;Stanley van Herk,&nbsp;Carla Exalto,&nbsp;Jasper E. Koenders,&nbsp;Patricia G. Hoogeveen,&nbsp;François G. Kavelaars,&nbsp;Anita M. Schelen,&nbsp;Willemijn van den Ancker,&nbsp;Arjan A. van de Loosdrecht,&nbsp;Charles G. Mullighan,&nbsp;H. Berna Beverloo,&nbsp;Vincent van der Velden,&nbsp;Jan J. Cornelissen,&nbsp;Peter J. M. Valk,&nbsp;Anita W. Rijneveld,&nbsp;Mathijs A. Sanders","doi":"10.1002/hem3.70195","DOIUrl":"https://doi.org/10.1002/hem3.70195","url":null,"abstract":"<p>Acute leukemia of ambiguous lineage (ALAL) is a rare, poor-prognosis acute leukemia subtype that cannot be assigned to a single hematopoietic lineage. Although ALAL patients are typically treated with acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) regimens, optimal treatment choice is hindered by their lineage ambiguity. Therefore, we investigated the added value of transcriptomics for improving lineage assignment, currently based mainly on surface markers. First, we used an in-house pipeline to detect genetic lesions in RNA sequencing data (<i>n</i> = 30) with a sensitivity &gt; 90% for small variants. Second, we compared ALAL gene expression profiles (GEPs) with representative AML (<i>n</i> = 145), B-ALL (<i>n</i> = 223), and T-ALL (<i>n</i> = 85) cases. In a principal component analysis (PCA), ALALs did not form a clear separate group, as most clustered with AML, B-ALL, or T-ALL. Accordingly, a machine learning classifier trained with GEPs of acute leukemias segregated 27/30 ALALs into myeloid-, B-, or T-lymphoid. These 27 cases harbored genetic abnormalities consistent with the classifier-assigned leukemia. Furthermore, deconvolution of ALAL GEPs revealed enrichment for signatures of normal hematopoietic cells corresponding to the leukemic type predicted by our algorithm. The classifier was also applied on an external ALAL cohort (<i>n</i> = 24), assigning 75% of the patients to a lineage matching their immunophenotypic and methylation profiles. In conclusion, integrative analysis of RNA sequencing data can accurately classify most ALAL cases as lineage-defined, while others show true transcriptional and epigenetic ambiguity driven by lesions like <i>BCL11B</i>. The pipeline and classifier developed here are valuable tools to improve ALAL diagnosis and guide therapeutic decisions.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 8","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70195","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144869832","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 peripheral blood and bone marrow MRD as prognostic markers in quadruplet-treated multiple myeloma without transplant","authors":"Benjamin A. Derman,&nbsp;Jennifer Cooperrider,&nbsp;Anna Pula,&nbsp;Heidi Simmons,&nbsp;Tadeusz Kubicki,&nbsp;Jeffrey Zonder,&nbsp;Aimaz Afrough,&nbsp;David Grinblatt,&nbsp;Jacalyn Rosenblatt,&nbsp;Larry D. Anderson Jr.,&nbsp;Andrew Kin,&nbsp;David Avigan,&nbsp;Sunil Narula,&nbsp;Shayan Rayani,&nbsp;Ken Jiang,&nbsp;Ajay Major,&nbsp;Theodore Karrison,&nbsp;Allison Jacob,&nbsp;Andrzej J. Jakubowiak","doi":"10.1002/hem3.70186","DOIUrl":"https://doi.org/10.1002/hem3.70186","url":null,"abstract":"&lt;p&gt;Assessing measurable residual disease (MRD) in the peripheral blood (PB) of patients with multiple myeloma (MM) could mitigate issues of patchy and/or extramedullary disease leading to false negative MRD tests based on bone marrow (BM)-only assessments and reduce patient discomfort associated with serial BM sampling. Early disease response assessment using serum protein electrophoresis and immunofixation may not be able to account for interference with therapeutic monoclonal antibodies such as daratumumab (Dara) and elotuzumab (Elo), nor do they account for the extended half-lives of immunoglobulins due to recycling. Identification of a PB assay that better reflects a patient's response status compared to the conventional International Myeloma Working Group (IMWG) response criteria&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; could enable a more informative response-adapted treatment approach as part of decision-making regarding consolidative strategies following induction. PB MRD by flow cytometry has previously been found to be an early prognostic marker among patients receiving triplet induction and was shown to be prognostic when utilized much later in the maintenance setting.&lt;span&gt;&lt;sup&gt;2, 3&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;In this analysis, we investigated the potential role and prognostic significance of early MRD status after four cycles of carfilzomib-based quadruplet induction therapy by next-generation sequencing (NGS) in both the BM and PB as well as by conventional IMWG response criteria.&lt;/p&gt;&lt;p&gt;This was a post hoc analysis from two multicenter Phase II studies investigating the efficacy and safety of elotuzumab, carfilzomib, lenalidomide, and dexamethasone (Elo-KRd) (NCT02969837) and Dara-KRd (NCT 03500445) in patients with newly diagnosed MM without transplant intent.&lt;span&gt;&lt;sup&gt;4, 5&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;In both studies, a landmark analysis was performed after Cycle 4 (C4), which included MRD evaluation by clonoSEQ (Adaptive Biotechnologies, Seattle) NGS (limit of detection 6.8 × 10&lt;sup&gt;−7&lt;/sup&gt; with input of 20 μg DNA) in BM and PB samples. MRD assessment by NGS was performed on PB or BM mononuclear cells for patients with available suitable material and with an identified dominant clonotype. MRD &lt; 10&lt;sup&gt;−6&lt;/sup&gt; in the BM was considered MRD negative, or MRD &lt; 10&lt;sup&gt;−5&lt;/sup&gt; if insufficient input to determine 10&lt;sup&gt;−6&lt;/sup&gt; status. PB mononuclear cells were evaluated for MRD using the same assay; any quantifiable signal was considered positive in PB. Conventional response was assessed per IMWG response criteria.&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;This landmark modified intent-to-treat (ITT) analysis focused on patients who remained on treatment at the end of C4 and had samples available for analysis (Supporting Information S1: Figure S1). Paired IMWG response and MRD status in the PB and BM were assessed for agreement and prognostic significance at the end of C4. Differences between groups were examined using the chi-square or Fisher's exact test. Agreement bet","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 8","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70186","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144869833","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":"Syntenin inhibition impairs stroma-tumor communication in multiple myeloma and improves bortezomib treatment efficiency","authors":"Chenggong Tu,&nbsp;Raphael Leblanc,&nbsp;Arne Van der Vreken,&nbsp;Marnix Koops,&nbsp;Stephane Audebert,&nbsp;Lauriane Goullieux,&nbsp;Sofie Meeussen,&nbsp;Kim De Veirman,&nbsp;Elke De Bruyne,&nbsp;Karin Vanderkerken,&nbsp;Guido David,&nbsp;Tom Cupedo,&nbsp;Pascale Zimmermann,&nbsp;Eline Menu","doi":"10.1002/hem3.70197","DOIUrl":"https://doi.org/10.1002/hem3.70197","url":null,"abstract":"<p>Multiple myeloma (MM) remains incurable due to the development of drug resistance. We previously showed that communication between bone marrow stromal cells (BMSCs) and MM cells supports MM growth and triggers therapy resistance. This communication occurs through a plethora of mechanisms, including the release of cytokines and small extracellular vesicles (sEVs). The PDZ protein syntenin is a master regulator of intercellular communication, in particular via sEVs. In this study, we aimed to explore whether targeting syntenin, by genetic alteration or pharmacological inhibition, can disrupt BMSC–MM crosstalk, thereby rendering the MM cells more sensitive to therapy. We found that syntenin (SDCBP) is highly expressed in inflammatory BMSC of MM patients and that its expression in BM aspirates correlates with poor patient survival. Using in vitro models, we established that knockout of syntenin in BMSC alters their secretome and abolishes BMSC-induced bortezomib resistance of MM cells via regulation of STAT3, MAPK, and AKT-mTOR pathways. Pharmacological inhibition of syntenin decreases syntenin and IL-6 sorting into BMSC sEVs and enhances bortezomib-induced MM cell death. Finally, we validated the therapeutic added value of syntenin inhibition in combination with bortezomib in vivo, using the 5TGM1 MM mouse model. In conclusion, our findings show that syntenin supports the secretion of pro-tumoral factors by BMSCs and qualifies as a possible novel therapeutic target in MM.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 8","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70197","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144861856","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":"Efficacy of idecabtagene vicleucel in patients with relapsed/refractory multiple myeloma and prior central nervous system manifestation: A multicenter real-world analysis","authors":"Markus Maulhardt,&nbsp;Simon Call,&nbsp;Hristo Boyadzhiev,&nbsp;Anca Maria Albici,&nbsp;Keven Hörster,&nbsp;Amelie Boquoi,&nbsp;Snjezana Janjetovic,&nbsp;Anna Ossami Saidy,&nbsp;Marcel Teichert,&nbsp;Annamaria Brioli,&nbsp;Christian Schultze-Florey,&nbsp;Florian Heidel,&nbsp;Philipp Schindler,&nbsp;Natalie Schub,&nbsp;Enver Aydilek,&nbsp;Matthias Stelljes,&nbsp;Michael Daskalakis,&nbsp;Carolin Krekeler,&nbsp;Justin Hasenkamp,&nbsp;Cyrus Khandanpour,&nbsp;Ulrike Bacher,&nbsp;Hans Christian Reinhardt,&nbsp;Georg Lenz,&nbsp;Friedrich Stölzel,&nbsp;Thomas Pabst,&nbsp;Bastian von Tresckow,&nbsp;Gerald Wulf,&nbsp;Philipp Berning,&nbsp;Evgenii Shumilov","doi":"10.1002/hem3.70192","DOIUrl":"https://doi.org/10.1002/hem3.70192","url":null,"abstract":"&lt;p&gt;Central nervous system (CNS) involvement in multiple myeloma (MM) is a rare complication associated with poor prognosis and a median overall survival (mOS) between 2 and 7 months.&lt;span&gt;&lt;sup&gt;1, 2&lt;/sup&gt;&lt;/span&gt; CNS involvement is characterized by plasma cell infiltration of the CNS parenchyma, meninges, or cerebrospinal fluid (CSF).&lt;span&gt;&lt;sup&gt;1, 3&lt;/sup&gt;&lt;/span&gt; B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T-cell therapies have significantly improved the treatment options for patients with relapsed/refractory (r/r) MM.&lt;span&gt;&lt;sup&gt;4, 5&lt;/sup&gt;&lt;/span&gt; Currently, two CAR T-cell products have been approved for r/r MM, ide-cel (idecabtagene vicleucel) and cilta-cel (ciltacabtagene autoleucel). With ide-cel being the first approved CAR T-cell therapy in r/r MM, it offers the longest clinical experience to date.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; Previous experience with CD19-directed CAR T-cells in patients (pts) with r/r large B-cell lymphomas and CNS involvement has demonstrated their ability to cross the blood–brain barrier, as well as to expand and persist in CNS compartments.&lt;span&gt;&lt;sup&gt;6-8&lt;/sup&gt;&lt;/span&gt; In contrast, for r/r MM pts with a history of CNS disease (MM-CNS), real-world evidence with respect to the efficacy and safety profiles of CAR T-cells remains limited, as these pts were excluded from the pivotal studies.&lt;span&gt;&lt;sup&gt;4, 5&lt;/sup&gt;&lt;/span&gt; To address this gap, we sought to evaluate the efficacy and toxicity profiles of BCMA-directed CAR T-cell therapy in MM-CNS pts in a real-world context.&lt;/p&gt;&lt;p&gt;We conducted a multicenter retrospective study including r/r MM pts undergoing ide-cel treatment between March 2022 and May 2024 at seven German/Swiss tertiary care centers. Pts were grouped by the presence of CNS disease before ide-cel infusion. Only pts with intradural and/or intraparenchymal lesions by magnetic resonance imaging (MRI)/computed tomography (CT) brain/spine or detection of myeloma cells in the CSF were regarded as MM-CNS pts. Descriptive and survival analyses, including propensity score matching (PSM) between MM-CNS and non-MM-CNS pts (optimal matching with 1:3 ratio; age at ide-cel, number of prior therapy lines, and IMWG response at ide-cel as covariates), were performed. Clinical data were gathered from the medical records.&lt;/p&gt;&lt;p&gt;Before CAR T-cell infusion, all patients received lymphodepleting chemotherapy with fludarabine and cyclophosphamide in accordance with guideline recommendations. Grading of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) was performed according to the American Society for Transplantation and Cellular Therapy consensus grading for CRS and ICANS.&lt;span&gt;&lt;sup&gt;9&lt;/sup&gt;&lt;/span&gt; The CNS response to CAR T-cell therapy was classified as complete remission (CR), partial remission (PR), stable disease (SD), and progressive disease (PD). The serologic response was assessed according to the established IMWG criteria.&lt;span&gt;&lt;sup&gt;10&lt;/sup&gt;&lt;/span&gt; The toxicit","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 8","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70192","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144861857","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":"Brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone for advanced-stage Hodgkin lymphoma in older patients","authors":"Paul J. Bröckelmann,&nbsp;Boris Böll,&nbsp;Daniel Molin,&nbsp;Gundolf Schneider,&nbsp;Sirpa Leppä,&nbsp;Julia Meissner,&nbsp;Peter Kamper,&nbsp;Martin Hutchings,&nbsp;Jacob H. Christensen,&nbsp;Ulf Schnetzke,&nbsp;Michael Fuchs,&nbsp;Janina Jablonski,&nbsp;Dennis A. Eichenauer,&nbsp;Bastian von Tresckow,&nbsp;Wolfram Klapper,&nbsp;Carsten Kobe,&nbsp;Peter Borchmann,&nbsp;Alexander Fosså","doi":"10.1002/hem3.70190","DOIUrl":"https://doi.org/10.1002/hem3.70190","url":null,"abstract":"<p>Historically, the outcomes among older patients with classic Hodgkin lymphoma (HL) have been inferior compared to younger patients, and 80% of HL-related deaths occur in patients ≥ 55 years of age at diagnosis.<span>¹</span> These inferior outcomes are in part attributable to comorbidities and frailty, resulting in poorer tolerability of standard multi-agent chemotherapies such as doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD).<span>²</span> Even if treatment is administered at standard relative dose intensities, lower progression-free survival (PFS) and overall survival (OS) are observed,<span>^{3, 4}</span> especially in patients with high comorbidity burden or impaired activities of daily living.<span>^{5, 6}</span> In light of demographic changes and increased life expectancy in many countries, the growing group of older patients hence constitutes a growing unmet need.<span>⁷</span></p><p>Recently, encouraging results were reported from subgroup analyses and a Phase II trial incorporating either brentuximab vedotin (BV) or nivolumab into first-line treatment.<span>⁸</span> Prospective clinical trials specifically designed to explore novel treatment options specifically in older HL patients remain however scarce. Moreover, patient-reported health-related quality of life (HRQoL) data in patients ≥ 60 years of age remain scarce to absent. Understanding the baseline HRQoL status and treatment-related trajectories in this patient population hence is of immediate interest.</p><p>In the international German Hodgkin Study Group (GHSG)-NLH intergroup Phase II BVB trial reported herein, we hypothesized that the combination of the anti-CD30 antibody–drug conjugate BV with cyclophosphamide, doxorubicin, and prednisone (B-CAP) constitutes a feasible and effective first-line treatment.</p><p>The Phase II trial (NCT02191930) evaluated six cycles of B-CAP (6xB-CAP), consisting of BV (1.8 mg/kg iv Day 1), cyclophosphamide (750 mg/m² iv d1), doxorubicin (50 mg/m² iv d1), and prednisone (100 mg po Days 2–6) at 3-weekly intervals as first-line treatment for advanced-stage HL patients ≥ 60 years considered eligible for combination chemotherapy. Patients provided written informed consent, and the trial was conducted according to Good Clinical Practice and in line with the Declaration of Helsinki. Further details are available in the Supplementary Methods.</p><p>Between 11/2015 and 09/2017, 50 patients were recruited at 17 centers in 5 European countries. One patient withdrew consent before the start of treatment, and a total of 49 patients with a median age of 66 years (range: 60–84, interquartile range [IQR] 64–70) were evaluable in the intention-to-treat population (Figure S1 and Table 1).</p><p>Before B-CAP treatment, 21 patients (43%) received a protocol-recommended corticosteroid pre-phase (100 mg prednisone/day for ≤5 days). With a median duration of systemic tr","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 8","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70190","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144861858","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":"Autologous stem cell transplantation in NK/T-cell lymphoma: Prognostic impact of EBV-DNA in a multinational cohort—A study by the EBMT Lymphoma Working Party","authors":"Philipp Berning,&nbsp;Maud Ngoya,&nbsp;Won Seog Kim,&nbsp;Evgenii Shumilov,&nbsp;Depei Wu,&nbsp;Haiwen Huang,&nbsp;Anne Cairoli,&nbsp;Alessandra Tucci,&nbsp;Guillaume Dachy,&nbsp;Romain Gounot,&nbsp;Anne C. Wilke,&nbsp;Christof Scheid,&nbsp;Peter Dreger,&nbsp;Jose Luis Lopez Lorenzo,&nbsp;Adrian Bloor,&nbsp;Joanna Romejko-Jarosinska,&nbsp;Alain Gadisseur,&nbsp;Roland Schroers,&nbsp;Péter Reményi,&nbsp;Ludovic Gabellier,&nbsp;Monica Poiani,&nbsp;Khalid Halahleh,&nbsp;Jacques-Emmanuel Galimard,&nbsp;Georg Lenz,&nbsp;Anna Sureda,&nbsp;Ali Bazarbachi,&nbsp;Bertram Glass,&nbsp;Norbert Schmitz","doi":"10.1002/hem3.70184","DOIUrl":"https://doi.org/10.1002/hem3.70184","url":null,"abstract":"<p>Natural killer (NK)/T-cell lymphomas (NKTCLs) are rare, aggressive lymphomas prevalent in East Asia and South America. Despite improvements, largely due to asparaginase-based therapies, outcomes for advanced disease remain poor, and the role of autologous stem cell transplantation (auto-HCT) remains controversial. This study evaluated real-world outcomes of auto-HCT in NKTCL patients across Asia and Europe. We included 130 adult NKTCL patients undergoing auto-HCT between 2011 and 2022 using data from the European Society for Blood and Marrow Transplantation (EBMT) registry and South Korean registry data. Median age was 51.3 years; 66.9% were male. Most patients (95.1%) had an Eastern Cooperative Oncology Group (ECOG) score 0–1; 65.3% had Stage III–IV disease. One prior therapy line was reported in 53.1%, and ≥2 lines in 46.9%. Asparaginase-based regimens were used in 79.5% pretransplant. Responses at auto-HCT included complete (59.7%), partial (27.9%) remission, and stable/progressive disease (12.4%). Epstein–Barr virus (EBV)-DNA in the peripheral blood was reported in 37.3%. With a median follow-up of 4.6 years, 3-year overall survival (OS) and progression-free survival (PFS) were 63.8% and 47.6%. Relapse and NRM rates at 3 years were 46.7% and 5.7%. Patients in complete remission had improved 3-year OS (75.2%) compared to PR (52.8%) and stable/progressive disease (32.0%) (P = 0.007). Detectable EBV-DNA in the blood at auto-HCT was associated with poor outcomes (3-year OS: 26.7% vs. 78.1% in patients with undetectable EBV-DNA; P &lt; 0.0001). Patients achieving complete remission and undetectable EBV-DNA in the blood before auto-HCT had a favorable survival, suggesting auto-HCT may be a treatment option in selected high-risk patients. This is the largest multinational cohort evaluating prognostic factors for auto-HCT for NKTCL.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 8","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70184","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144843561","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":"Inhibiting the alarmin-driven hematopoiesis-stromal cell crosstalk in primary myelofibrosis ameliorates bone marrow fibrosis","authors":"Hélène F. E. Gleitz,&nbsp;Stijn N. R. Fuchs,&nbsp;Inge A. M. Snoeren,&nbsp;Charlotte Boys,&nbsp;James Nagai,&nbsp;Hector Tejeda-Mora,&nbsp;Vanessa Klöker,&nbsp;Jessica E. Pritchard,&nbsp;Iris J. Bakker,&nbsp;Marta Gargallo Garasa,&nbsp;Eric Bindels,&nbsp;Julio Saez-Rodriguez,&nbsp;Thomas Vogl,&nbsp;Rafael Kramann,&nbsp;Aurélien Dugourd,&nbsp;Ivan G. Costa,&nbsp;Rebekka K. Schneider","doi":"10.1002/hem3.70179","DOIUrl":"https://doi.org/10.1002/hem3.70179","url":null,"abstract":"<p>Inflammation from the hematopoietic compartment is a critical driver of fibrosis and cytopenias in myeloproliferative neoplasms (MPNs). We previously demonstrated that tasquinimod ameliorates the MPN phenotype, reducing splenomegaly and normalizing fibrosis in a JAK2V617F-driven preclinical model. Using bulk RNA sequencing, we now show that tasquinimod primarily targets the malignant JAK2V617F hematopoietic clone, particularly affecting megakaryocytes and monocytes. Tasquinimod downregulates pro-proliferative pathways, MYC targets, and mTORC signaling, while increasing apoptosis in particularly in JAK2V617F mutant cells. Our data reveal that tasquinimod reverses TGFβ-driven fibrotic reprogramming of megakaryocytes and monocytes. This reversal is crucial for mitigating the pro-fibrotic interactions and signaling in the BM, thereby decreasing the activation of stromal cells. Coculture experiments confirm that direct interaction between JAK2V617F hematopoietic cells and mesenchymal stromal cells upregulates S100A8 in stromal cells, independent of TGFβ alone. In line, genetic ablation of S100A9 in the hematopoietic but not stromal compartment significantly improves the MPN phenotype and normalizes BM fibrosis. Our data highlight the hematopoietic origin of the inflammatory signals driving fibrosis. These insights pave the way for potential therapeutic strategies targeting inflammatory signaling pathways in MPN to mitigate fibrosis and improve patient outcomes.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 8","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70179","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144833173","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":"3D Tumor microenvironment interaction reveals AP-1 complex regulation and contact-mediated reprogramming of bone marrow stromal cells in chronic lymphocytic leukemia","authors":"Jana Lindacher,&nbsp;Anne Hartebrodt,&nbsp;Janin Dingfelder,&nbsp;Pascal Lukas,&nbsp;Laeschkir Würthner,&nbsp;Simon Völkl,&nbsp;David B. Blumenthal,&nbsp;Frederik Graw,&nbsp;Kerstin Amann,&nbsp;Manuela Krumbholz,&nbsp;Martina Haibach,&nbsp;Jochen Wilke,&nbsp;Andreas Mackensen,&nbsp;Gloria Lutzny-Geier","doi":"10.1002/hem3.70199","DOIUrl":"https://doi.org/10.1002/hem3.70199","url":null,"abstract":"<p>Chronic lymphocytic leukemia (CLL) cells actively reprogram their tumor microenvironment (TME) to promote drug resistance and tumor progression. Tumor cell survival critically depends on heterotypic communication with benign cells in the microenvironment, particularly bone marrow-derived stromal cells (BMSCs). Our three-dimensional (3D) approach allows us to investigate spatially defined, mutual direct cell–cell interactions between CLL B cells, autologous T cells, and BMSCs, forming complex scaffold-like structures reminiscent of in vivo conditions. Here, we observe that CLL B cells localized in the core regions of 3D structures upregulate the AP-1 transcription factor complex, which confers significant protection against therapy-induced cell death. Additionally, regulatory T cells (T_reg) and follicular T helper cells (T_fH) are more abundant in the core regions. CLL B cells, in turn, induce contact-mediated reprogramming of BMSCs, resulting in a novel, distinct BMSC population with inflammation, bone immune evasion, and cancer-associated fibroblast-like features. Our findings reveal critical mechanisms by which CLL cells exploit the TME to drive pathogenesis and therapeutic resistance using realistic 3D setups, highlighting the potential of targeting AP-1 and the stromal compartment in future treatment strategies.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 8","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70199","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144832896","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":"Inflammatory signaling in the pathogenesis of acute myeloid leukemia","authors":"Artemis Margrith Baumann,&nbsp;Jana Maria Ellegast","doi":"10.1002/hem3.70188","DOIUrl":"https://doi.org/10.1002/hem3.70188","url":null,"abstract":"<p>Acute myeloid leukemia (AML) is a heterogeneous clonal disorder of hematopoietic stem and progenitor cells and the most common malignant myeloid disorder in adults. Extensive research has elucidated the broad spectrum of biological mechanisms contributing to the development of AML and specifically characterized a variety of genetic alterations initiating and defining the disease. However, the role of inflammation in the pathogenesis of AML remains relatively unexplored; indeed, studies on the contribution of inflammatory signaling to disease initiation in myeloid malignancies have only recently gained attention, marking an emerging area of research. AML has the highest incidence in the elderly, where inflammation plays an even greater role. A granular understanding of inflammatory processes driving leukemogenesis thus promises to guide therapeutic strategies for a patient population where outcomes remain dismal. This review offers a comprehensive synthesis of the current knowledge on the role of inflammatory signaling in AML pathogenesis. It discusses the role of inflammation from premalignant states through malignant transformation, dissecting phenotypic, correlative studies from mechanistic evidence. We thereby highlight questions requiring further research to exploit the translational potential of therapies targeting inflammatory signaling and to address challenges with current immune-modulating treatments. A particular focus is placed on assessing the role of inflammation in the interplay with genetic events as established factors in disease initiation and progression to clarify the current understanding of inflammatory signaling in AML pathogenesis.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 8","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70188","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144832892","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":"Arsenic trioxide for reprogramming the bone marrow microenvironment to eliminate acute myeloid leukemia blasts","authors":"David Kegyes,&nbsp;Patric Teodorescu,&nbsp;Teodora Supeanu,&nbsp;Yuya Nagai,&nbsp;Guo Zhong,&nbsp;Vikram Mathews,&nbsp;Nina Isoherranen,&nbsp;Gabriel Ghiaur","doi":"10.1002/hem3.70191","DOIUrl":"https://doi.org/10.1002/hem3.70191","url":null,"abstract":"&lt;p&gt;Acute myeloid leukemia (AML) is characterized by the uncontrolled proliferation of immature myeloid cells. Traditional chemotherapy has been the cornerstone of AML treatment for decades.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; The introduction of targeted therapies, such as FLT3 tyrosine kinase inhibitors (FLT3TKIs) and IDH inhibitors (IDHi), has improved outcomes for specific AML subtypes. Currently, up to 80% of patients achieve morphologic complete remission (CR) at the end of induction.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; However, most relapse and die, largely due to the persistence of minimal residual disease (MRD). Understanding the mechanisms behind MRD persistence is paramount for improving survival for these patients. Evidence increasingly shows that the bone marrow microenvironment (BME) plays a central role in the persistence of MRD.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; BME-dependent drug resistance includes agent-specific mechanisms (e.g., activation of alternative signaling pathways)&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; and broader resistance (e.g., impaired pharmacokinetics, PKs).&lt;span&gt;&lt;sup&gt;4, 5&lt;/sup&gt;&lt;/span&gt; Currently, eliminating MRD and thus, achieving a cure requires multiple chemotherapy cycles or bone marrow (BM) transplantation. Targeting driver mutations alone is insufficient to eradicate MRD.&lt;/p&gt;&lt;p&gt;A notable exception is acute promyelocytic leukemia (APL), driven by the PML-RARA fusion oncoprotein, the product of t(15;17). Targeting PML-RARA with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) virtually eliminates relapse,&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; even though each agent alone is suboptimal. Both ATRA and ATO bind to different parts of PML-RARA. ATRA binds RARA, restores retinoid-dependent transcription, and induces differentiation.&lt;span&gt;&lt;sup&gt;7&lt;/sup&gt;&lt;/span&gt; However, single-agent ATRA results in “remission without cure,” with nearly 100% relapse rates.&lt;span&gt;&lt;sup&gt;8&lt;/sup&gt;&lt;/span&gt; This is due to BME-expressed CYP26, an enzyme that degrades ATRA, impairing ATRA PKs in the BM.&lt;span&gt;&lt;sup&gt;9-11&lt;/sup&gt;&lt;/span&gt; Retinoids directly upregulate stromal CYP26, creating a retinoid-free niche that allows MRD to persist.&lt;span&gt;&lt;sup&gt;12&lt;/sup&gt;&lt;/span&gt; Liposomal ATRA, which improves ATRA tissue distribution, has been more effective in reducing relapse, highlighting the role of ATRA PKs in MRD persistence in APL.&lt;span&gt;&lt;sup&gt;13&lt;/sup&gt;&lt;/span&gt; The biochemical barrier created by the BME can also be bypassed using CYP26-resistant retinoids or inhibiting CYP26.&lt;span&gt;&lt;sup&gt;11, 12, 14, 15&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;ATO also directly binds PML-RARA, leading to ubiquitination and degradation of the fusion protein.&lt;span&gt;&lt;sup&gt;16&lt;/sup&gt;&lt;/span&gt; However, single-agent ATO does not fully eliminate MRD, with relapse rates around 30%.&lt;span&gt;&lt;sup&gt;17, 18&lt;/sup&gt;&lt;/span&gt; By binding distinct PML-RARA regions, ATRA and ATO synergistically eliminate leukemic blasts to achieve CR. The mechanism of this synergy within the “retinoid-free” BM niche is unclear. A possible explanation is that ATO enhances ATRA PKs, improving retinoid bi","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 8","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70191","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144811005","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}