Experimental hematology最新文献_第2页

Evaluation of dual BCL-2/BCL-XL inhibition in acute myeloid leukemia preclinical models with and without prior venetoclax therapy 评估双重BCL-2/BCL-XL抑制AML临床前模型有和没有先前venetoclax治疗。

IF 2.1 4区医学

Experimental hematology Pub Date : 2026-04-01 Epub Date: 2026-01-12 DOI: 10.1016/j.exphem.2026.105379

Reecha Shah , Nathan Kingston , Giulia Fabbri , Jamal Saeh , Courtney Andersen , Patricia Cheung

{"title":"Evaluation of dual BCL-2/BCL-XL inhibition in acute myeloid leukemia preclinical models with and without prior venetoclax therapy","authors":"Reecha Shah , Nathan Kingston , Giulia Fabbri , Jamal Saeh , Courtney Andersen , Patricia Cheung","doi":"10.1016/j.exphem.2026.105379","DOIUrl":"10.1016/j.exphem.2026.105379","url":null,"abstract":"<div><div>Acute myeloid leukemia (AML) is an aggressive hematologic malignancy that relies heavily on the antiapoptotic protein B-cell lymphoma 2 (BCL-2) for survival. Venetoclax, a BCL-2 inhibitor, exploits this dependency and is currently approved for treatment of elderly patients with AML. BCL-XL, another prosurvival protein in the BCL-2 family, has been identified as a key driver of both intrinsic and acquired resistance to venetoclax. Patients often develop resistance to BCL-2 inhibition through upregulation of BCL-XL. This study investigates the efficacy of a dual BCL-2/BCL-XL inhibitor and its combination with standard-of-care (SOC) agents. Dual BCL-2/BCL-XL inhibitor demonstrates robust activity in AML cell lines and patient-derived models, including activity in samples from patients who relapsed following venetoclax therapy. Its combination with SOC agents deepens the antileukemic activity both in vitro and in vivo. Among the combination regimens tested, cytarabine or hypomethylating agents (HMAs) drive strong blast reduction in patient samples previously exposed to venetoclax and yield improved survival in xenograft models derived from patients with AML who underwent prior venetoclax/5-azacytidine treatment. These preclinical findings support the clinical evaluation of dual BCL-2/BCL-XL inhibition in patients with AML, particularly, those who do not respond to venetoclax.</div></div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"156 ","pages":"Article 105379"},"PeriodicalIF":2.1,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145984639","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Anti-IL-18 immunotherapy decreases inflammatory and vaso-occlusive responses in mice with sickle cell disease 抗il -18免疫疗法可降低镰状细胞病小鼠的炎症和血管闭塞反应。

IF 2.1 4区医学

Experimental hematology Pub Date : 2026-04-01 Epub Date: 2025-12-31 DOI: 10.1016/j.exphem.2025.105366

Érica M.F. Gotardo , Lidiane S. Torres , Irmgard Förster , Lucas F.S. Gushiken , Pâmela L. Brito , Flavia C. Leonardo , Bruna Cunha Zaidan , Andreas Bruederle , Sergei Agoulnik , Jiri Kovarik , John Millholland , Fernando F. Costa , Nicola Conran

{"title":"Anti-IL-18 immunotherapy decreases inflammatory and vaso-occlusive responses in mice with sickle cell disease","authors":"Érica M.F. Gotardo , Lidiane S. Torres , Irmgard Förster , Lucas F.S. Gushiken , Pâmela L. Brito , Flavia C. Leonardo , Bruna Cunha Zaidan , Andreas Bruederle , Sergei Agoulnik , Jiri Kovarik , John Millholland , Fernando F. Costa , Nicola Conran","doi":"10.1016/j.exphem.2025.105366","DOIUrl":"10.1016/j.exphem.2025.105366","url":null,"abstract":"<div><div>Sickle cell disease (SCD) is characterized by inflammatory and vaso-occlusive processes that drive acute crises and progressive organ damage. Interleukin-18 (IL-18), elevated in patients with SCD and mouse models, contributes to these pathological mechanisms. We evaluated the effects of acute and prolonged IL-18 blockade using the SK113AE-4 monoclonal antibody in Townes and Berkeley SCD mice. Acute IL-18 neutralization reduced tumor necrosis factor-alpha (TNF-α)-induced microvascular leukocyte recruitment and prevented hypoperfusion, indicating that modulation of inflammatory signaling improves physiological responses in SCD. Prolonged anti-IL-18 immunotherapy for 6 weeks decreased circulating TNF-α and IL-10 and reduced hepatic macrophage infiltration, but did not prevent liver fibrosis, iron deposition, or alter biochemical markers of hemolysis or hepatic/renal injury. As such, IL-18 blockade attenuates vascular inflammation and vaso-occlusive-like events but may be insufficient to prevent SCD-related liver injury under the conditions tested. In contrast, in our previous study, anti-IL-1β immunotherapy provided added liver protection, highlighting potentially divergent cytokine pathways in SCD. Collectively, these results support IL-18 as a therapeutic target to reduce vascular inflammation and vaso-occlusive processes, and suggest that combined inflammasome cytokine-targeted or multiapproach strategies may be required to prevent organ damage in SCD.</div></div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"156 ","pages":"Article 105366"},"PeriodicalIF":2.1,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145892358","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Gene therapy acceptance in a high-consanguinity sickle cell disease population: bridging genetic literacy to therapeutic innovation in Saudi Arabia 基因治疗在高血缘镰状细胞病人群中的接受度：在沙特阿拉伯连接基因素养与治疗创新。

IF 2.1 4区医学

Experimental hematology Pub Date : 2026-04-01 Epub Date: 2026-01-22 DOI: 10.1016/j.exphem.2026.105380

Khaled Essawi

{"title":"Gene therapy acceptance in a high-consanguinity sickle cell disease population: bridging genetic literacy to therapeutic innovation in Saudi Arabia","authors":"Khaled Essawi","doi":"10.1016/j.exphem.2026.105380","DOIUrl":"10.1016/j.exphem.2026.105380","url":null,"abstract":"<div><div>The Jazan region of Saudi Arabia has a high prevalence of sickle cell disease (SCD), compounded by consanguineous marriages. The Jazan region exemplifies a population that is markedly underrepresented in genomic medicine research, distinguished by distinctive sociocultural factors, including consanguinity rates surpassing one half. Although gene therapy (GT) offers a potential cure, its implementation requires an understanding of local awareness and acceptance. A cross-sectional online survey of 357 Jazan residents, including 104 individuals/families affected with SCD, assessed genetic literacy, clinical burden, and GT attitudes. Multivariate logistic regression identified predictors of GT awareness and acceptance. Despite high genetic literacy (84.0% knew SCD inheritance; 72.5% were aware of consanguinity risks), only 45.4% were aware of GT. Graduate education (odds ratio [OR], 3.54; 95% confidence interval [CI], 1.80–6.95) and personal SCD status (OR, 1.97; 95% CI, 1.15–3.37) independently predicted GT awareness. Among affected individuals, GT acceptance was independently predicted by awareness of consanguinity risk (OR, 3.51; 95% CI, 1.25–9.80) and personal SCD status (OR, 2.89; 95% CI, 1.08–7.74). This educated cohort exhibits a significant gap between genetic knowledge and GT awareness. Acceptance is strongly driven by an understanding of inheritance patterns, highlighting the need for genetic counseling that links consanguinity risks to therapeutic advances to facilitate equitable GT implementation.</div></div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"156 ","pages":"Article 105380"},"PeriodicalIF":2.1,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146043761","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Taking the direct route: menin inhibitors go straight to the frontline in KMT2A-rearranged acute leukemia 采取直接途径：menin抑制剂直接进入kmt2a重排急性白血病的前线。

IF 2.1 4区医学

Experimental hematology Pub Date : 2026-04-01 Epub Date: 2026-02-04 DOI: 10.1016/j.exphem.2026.105386

Anjum B. Khan , Brian J.P. Huntly

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Polycomb repressive complexes as therapeutic targets in hematologic malignancies 多梳抑制复合物作为血液系统恶性肿瘤的治疗靶点。

IF 2.1 4区医学

Experimental hematology Pub Date : 2026-03-01 Epub Date: 2025-12-22 DOI: 10.1016/j.exphem.2025.105339

Makoto Yamagishi , Atsushi Iwama , Issay Kitabayashi

{"title":"Polycomb repressive complexes as therapeutic targets in hematologic malignancies","authors":"Makoto Yamagishi , Atsushi Iwama , Issay Kitabayashi","doi":"10.1016/j.exphem.2025.105339","DOIUrl":"10.1016/j.exphem.2025.105339","url":null,"abstract":"<div><div>Polycomb-group proteins form PRC1 and PRC2 complexes that mediate heritable transcriptional repression via H2AK119 ubiquitination and H3K27 trimethylation. Canonical PRC1 catalyzes H2AK119 monoubiquitination through RING1A/B, whereas PRC2 deposits H3K27me3 via EZH1/2. Variant PRC1 (vPRC1) and PRC2 subtypes use distinct recruitment mechanisms, enabling both PRC2-dependent and -independent silencing. In hematopoiesis, components of PRC1, such as BMI1, and those of PRC1.1, including BCOR and PCGF1, have been well characterized for their roles in governing hematopoietic stem cell (HSC) self-renewal and lineage specification. Similarly, PRC2 components, particularly EZH1/2, SUZ12, and EED, are essential for the maintenance of HSCs. Aberrations in PRC1/2, such as gain- or loss-of-function mutations in <em>EZH2</em> and loss-of-function mutations in <em>BCOR</em>, drive hematologic malignancies, including acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and lymphomas. In malignant lymphoma, mutations in chromatin regulators (e.g., <em>EZH2, KMT2D</em>, and <em>CREBBP</em>) reshape the epigenetic landscape, disrupting differentiation and immune recognition. Elevated H3K27me3 represents an early and shared epigenetic feature across diverse subclones in lymphoid neoplasms, including adult T-cell leukemia/lymphoma (ATL). Therapeutic targeting of H3K27me3 with EZH2-selective inhibitors such as tazemetostat has shown clinical benefit in lymphoma; however, their efficacy is limited by functional redundancy with EZH1. The dual EZH1/2 inhibitor valemetostat overcomes this limitation by reactivating tumor-suppressor genes, achieving durable responses in ATL and peripheral T-cell lymphoma (PTCL). Nonetheless, therapeutic resistance can emerge through PRC2 gatekeeper mutations and compensatory DNA methylation. These findings underscored the value of targeting the dysregulated epigenome and support the continued clinical development of dual EZH1/2 inhibitors.</div></div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"155 ","pages":"Article 105339"},"PeriodicalIF":2.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145827156","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Tumor necrosis factor from leukemic environment stimulates hematopoietic stem/progenitor cells toward megakaryocyte/myeloid lineage bias 来自白血病环境的肿瘤坏死因子刺激造血干细胞/祖细胞向巨核细胞/髓细胞谱系倾斜。

IF 2.1 4区医学

Experimental hematology Pub Date : 2026-03-01 Epub Date: 2025-12-04 DOI: 10.1016/j.exphem.2025.105332

Hidekazu Nishikii , Riko Kikuchi , Takaharu Kimura , Mizuki Saito , Yusuke Kiyoki , Saki Tanaka , Yamato Sasaki , Takayasu Kato , Tatsuhiro Sakamoto , Mamiko Sakata-Yanagimoto , Naoshi Obara , Satoshi Yamazaki , Shigeru Chiba

{"title":"Tumor necrosis factor from leukemic environment stimulates hematopoietic stem/progenitor cells toward megakaryocyte/myeloid lineage bias","authors":"Hidekazu Nishikii , Riko Kikuchi , Takaharu Kimura , Mizuki Saito , Yusuke Kiyoki , Saki Tanaka , Yamato Sasaki , Takayasu Kato , Tatsuhiro Sakamoto , Mamiko Sakata-Yanagimoto , Naoshi Obara , Satoshi Yamazaki , Shigeru Chiba","doi":"10.1016/j.exphem.2025.105332","DOIUrl":"10.1016/j.exphem.2025.105332","url":null,"abstract":"<div><div>Acute myeloid leukemia (AML) is characterized by the proliferation of malignant myeloid progenitor cells and impairment of hematopoiesis. Although genetic abnormalities within leukemic cells have been investigated in detail, definitive explanations for the damage to the normal hematopoietic system are lacking. Here, we investigated the mechanisms underlying the impairment of the residual hematopoietic system in the bone marrow in AML. We evaluated the function of residual nonleukemic (nl)-hematopoietic stem/progenitor cells (HSPCs) from the bone marrow of mice with MLL-AF9-induced AML. The nl-HSPCs in the leukemic marrow showed a megakaryocyte (MgK) and myeloid-biased gene expression signature, with enrichment of tumor necrosis factor (TNF) signaling and reduced repopulation ability. To investigate whether the upregulation of TNF signaling causes the MgK/myeloid lineage bias, we investigated the effects of TNF-α in normal hematopoietic stem cells (HSCs)/HSPCs under ex vivo expansion condition. Single-cell transcriptome analysis of these cells revealed an increased frequency of cells expressing genes related to the MgK lineage and decreased repopulation capacity compared with those of ex vivo expanded HSCs/HSPCs without TNF-α. Our data suggest that increased TNF-α in the leukemic bone marrow environment at least in part drives HSPCs toward MgK/myeloid differentiation, resulting in the exhaustion of residual normal HSCs/HSPCs. These findings offer valuable insights into leukemic biology and normal hematopoiesis.</div></div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"155 ","pages":"Article 105332"},"PeriodicalIF":2.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145696010","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Loss of Ezh2 precipitates lethal disease progression in a mouse model of Calr-mutated myeloproliferative neoplasms 在calr突变的骨髓增殖性肿瘤小鼠模型中，Ezh2的缺失加速了致命的疾病进展。

IF 2.1 4区医学

Experimental hematology Pub Date : 2026-03-01 Epub Date: 2025-12-13 DOI: 10.1016/j.exphem.2025.105350

Koki Ueda , Yuka Sato , Keiji Minakawa , Saori Miura , Yuko Hashimoto , Kazuhiko Ikeda

{"title":"Loss of Ezh2 precipitates lethal disease progression in a mouse model of Calr-mutated myeloproliferative neoplasms","authors":"Koki Ueda , Yuka Sato , Keiji Minakawa , Saori Miura , Yuko Hashimoto , Kazuhiko Ikeda","doi":"10.1016/j.exphem.2025.105350","DOIUrl":"10.1016/j.exphem.2025.105350","url":null,"abstract":"<div><div>Patients with <em>CALR</em>-mutant essential thrombocythemia (ET), the myeloproliferative neoplasm (MPN) subtype with the most favorable long-term prognosis, remain at risk of developing secondary myelofibrosis (sMF) or acute myeloid leukemia (AML). Outcomes after such progression are poor. Loss-of-function mutations in the epigenetic regulator <em>EZH2</em> are frequently acquired during disease evolution, but their causal contribution to <em>CALR</em>-driven MPN has remained uncertain. To investigate this question, we used a knock-in mouse that constitutively expresses a <em>Calr</em> frameshift allele and introduced conditional <em>Ezh2</em> deletion triggered by tamoxifen. <em>Ezh2</em> loss in <em>Calr</em>-mutant MPN resulted in lethal disease progression. These mice developed two terminal outcomes that mirror human disease: fibrotic MPN (sMF-like) and blast-phase MPN (AML-like). Transplantation experiments demonstrated that only the AML-like phenotype was transplantable, whereas the sMF-like phenotype did not confer lethal condition in recipients. These findings provide direct in vivo evidence that <em>EZH2</em> loss drives malignant evolution of <em>CALR</em>-mutant MPN. Transcriptomic profiling of leukemic stem cells from AML-like mice revealed enrichment of fatty acid oxidation (FAO) pathways. Short-term colony assays showed that inhibition of peroxisome proliferator-activated receptor-γ (PPARγ) modestly increased the antiproliferative effect of cytarabine on AML-derived stem and progenitor cells, suggesting a possible reliance on FAO. Reanalysis of public single-cell RNA-sequencing data from patients with MPN progressing to AML also demonstrated elevated FAO signatures in leukemic stem cells. Together, these results identify <em>EZH2</em> loss as a key determinant of <em>CALR</em>-mutant MPN progression and point to altered metabolic wiring as a potential vulnerability in post-MPN AML.</div></div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"155 ","pages":"Article 105350"},"PeriodicalIF":2.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145762587","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Hematopoietic stem cell-independent and -dependent hematopoiesis: new insights and lineage-tracing methods 造血干细胞独立和依赖造血：新的见解和谱系追踪方法。

IF 2.1 4区医学

Experimental hematology Pub Date : 2026-03-01 Epub Date: 2025-12-13 DOI: 10.1016/j.exphem.2025.105352

Miguel Ganuza , Momoko Yoshimoto

引用次数: 0

Laminin receptor characterization in acute myeloid leukemia: integrin α7β1 defines leukemic cells with migratory potential 急性髓系白血病层粘连蛋白受体特征：整合素α7β1决定白血病细胞的迁移潜能。

IF 2.1 4区医学

Experimental hematology Pub Date : 2026-03-01 Epub Date: 2025-12-25 DOI: 10.1016/j.exphem.2025.105363

Elsa Görsch , Saskia Simone Rudat , Marlon Arnone , Hildegard Keppeler , Nandini Asokan , Jan C. Schröder , Taylor Scott Mills , Lucas Mix , Lea Kramer , Jan Pauluschke-Fröhlich , Maksim Klimiankou , Jan Weller , Gerd Klein , Claudia Lengerke

{"title":"Laminin receptor characterization in acute myeloid leukemia: integrin α7β1 defines leukemic cells with migratory potential","authors":"Elsa Görsch , Saskia Simone Rudat , Marlon Arnone , Hildegard Keppeler , Nandini Asokan , Jan C. Schröder , Taylor Scott Mills , Lucas Mix , Lea Kramer , Jan Pauluschke-Fröhlich , Maksim Klimiankou , Jan Weller , Gerd Klein , Claudia Lengerke","doi":"10.1016/j.exphem.2025.105363","DOIUrl":"10.1016/j.exphem.2025.105363","url":null,"abstract":"<div><div>Interactions with the bone marrow (BM) niche are crucial for promoting self-renewal and survival of acute myeloid leukemia (AML) cells. Consequently, AML cells express a variety of surface receptors to engage with BM niche cells and extracellular matrix proteins, including laminins. Despite the association of laminin receptors with stemness in healthy hematopoiesis, their role in AML remains poorly understood. In this study, we present a comprehensive examination of the laminin receptors integrin α3β1, α6β1, α7β1, and basal cell adhesion molecule (BCAM) in AML. We demonstrate that high messenger RNA (mRNA) expression of all four laminin receptors correlates with poor overall survival. Notably, integrin α6 (ITGA6) and integrin α7 (ITGA7) display the highest cell surface density among the examined laminin receptors and are more highly expressed on AML cells compared with healthy controls. Moreover, our results indicate that the absence of ITGA7 expression can identify cells with increased colony-forming potential, even in patients who are negative for the stem cell marker CD34, usually used to enrich leukemic stem cells (LSCs). Reanalyzing survival data from The Cancer Genome Atlas (TCGA)-AML cohort, <em>ITGA7</em> expression further allows refinement of the risk stratification based on the LSC score, where low LSC and <em>ITGA7</em> levels confer superior survival. Lastly, ITGA7 appears to mark leukemic cells with enhanced migratory potential, which can be inhibited by the anti-ITGA7 blocking antibody in vitro and in vivo. Together, our results confirm the association of high laminin receptor expression with poor prognosis and ITGA7 as a marker of high migratory leukemic cells.</div></div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"155 ","pages":"Article 105363"},"PeriodicalIF":2.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145846280","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

IFC Editorial Board IFC编委会

IF 2.1 4区医学

Experimental hematology Pub Date : 2026-03-01 Epub Date: 2026-02-18 DOI: 10.1016/S0301-472X(26)00022-6

引用次数: 0