Experimental hematology最新文献_第2页

Sex differences alter primitive progenitors in the C57BL/6 Tet2 knockout mouse model.

IF 2.5 4区医学

Experimental hematology Pub Date : 2025-02-25 DOI: 10.1016/j.exphem.2025.104747

Samantha M Holmes, Christopher J Wells, Christine Hall, Amy J M McNaughton, Michael J Rauh, Sheela A Abraham

{"title":"Sex differences alter primitive progenitors in the C57BL/6 Tet2 knockout mouse model.","authors":"Samantha M Holmes, Christopher J Wells, Christine Hall, Amy J M McNaughton, Michael J Rauh, Sheela A Abraham","doi":"10.1016/j.exphem.2025.104747","DOIUrl":"10.1016/j.exphem.2025.104747","url":null,"abstract":"<p><p>The precancerous expansion of hematopoietic cells, termed clonal hematopoiesis (CH), has been correlated to disease development and all-cause mortality. Despite multiple observations that hematopoietic stem cell and progenitors (HSPCs) are significantly affected by both sex and age, there remain few studies quantifying male and female HSPC populations in wild-type and transgenic Tet2 models over time. Here, we determine that male mice (with a hematopoietic deficiency of Tet2 and control) have more Lin<sup>-</sup>Sca-1<sup>+</sup>c-kit<sup>+</sup> (LSK) cells, that include multipotent progenitor cells (MPPs; LSK CD48<sup>-</sup>CD150<sup>-</sup>) and long-term hematopoietic stem cells (LT-HSC; LSK CD48<sup>-</sup>CD150<sup>+</sup>) compared with females. LT-HSC, MPP, and progenitor populations were observed to possess equal male/female ratios in mice at 6 weeks of age; however, the LSK compartment was found most susceptible to sex-based effects in transgenic mice between 6 weeks and 4 months. In contrast, all differentiated progenitor populations analyzed in mice were observed to be unaffected by sex between 6 weeks to 4 months. This study provides a comprehensive analysis of bone-sourced HSPCs in Tet2-deficient mouse models and reveals important sex and age considerations that must be taken into account when using C57BL/6 mice for transgenic studies.</p>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":" ","pages":"104747"},"PeriodicalIF":2.5,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143523041","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

D816V KIT mutation induces mitochondrial morphologic and functional changes through BNIP3 downregulation in human myeloid cell lines ROSA and TF-1

IF 2.5 4区医学

Experimental hematology Pub Date : 2025-02-20 DOI: 10.1016/j.exphem.2025.104748

Sabina Cisa-Wieczorek , Maria Isabel Hernández-Alvarez , Matilde Parreño , Juan P. Muñoz , Elena Bussaglia , Maite Carricondo , Jose Ubeda , Patrice Dubreuil , Antonio Zorzano , Fabienne Brenet , Josep F. Nomdedeu

{"title":"D816V KIT mutation induces mitochondrial morphologic and functional changes through BNIP3 downregulation in human myeloid cell lines ROSA and TF-1","authors":"Sabina Cisa-Wieczorek , Maria Isabel Hernández-Alvarez , Matilde Parreño , Juan P. Muñoz , Elena Bussaglia , Maite Carricondo , Jose Ubeda , Patrice Dubreuil , Antonio Zorzano , Fabienne Brenet , Josep F. Nomdedeu","doi":"10.1016/j.exphem.2025.104748","DOIUrl":"10.1016/j.exphem.2025.104748","url":null,"abstract":"<div><div>The KIT receptor is a transmembrane protein found on the surface of many different cell types. Mutant forms of KIT are drivers of myeloid neoplasms, including systemic mastocytosis. The KIT D816V mutation is the most common, leading to constitutive activation of the receptor and its downstream targets, and it is highly resistant to c-KIT inhibitors. Metabolic rewiring is a common trait in cancer. We analyzed the metabolic profile induced by the KIT D816 mutation, measuring mitochondrial parameters in two myeloid cell lines. We found that the KIT D816V mutation causes a significant increase in mitochondrial abundance and activity associated with superoxide production, which could promote DNA instability. Functional and morphologic changes in mitochondria were associated with reduced levels of BNIP3 protein expression. We also detected low BNIP3 levels in clinical acute myeloid leukemia samples harboring D816V mutations. In addition, we have found constitutive mTOR activation in mutated cells, a pathway that has been shown to regulate autophagy. Our data suggest that KIT D816V increases mitochondrial activity through downregulation of BNIP3 expression, which increases mitochondrial number through the autophagy pathway. Alterations in the cellular metabolism induced by the KIT D816V mutation could be therapeutically exploited.</div></div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"145 ","pages":"Article 104748"},"PeriodicalIF":2.5,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143476009","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

Bone marrow niches for hematopoietic stem cells in homeostasis and aging

IF 2.5 4区医学

Experimental hematology Pub Date : 2025-02-18 DOI: 10.1016/j.exphem.2025.104749

Taichi Nakatani, Takashi Nagasawa

{"title":"Bone marrow niches for hematopoietic stem cells in homeostasis and aging","authors":"Taichi Nakatani, Takashi Nagasawa","doi":"10.1016/j.exphem.2025.104749","DOIUrl":"10.1016/j.exphem.2025.104749","url":null,"abstract":"<div><div>Among various types of candidate cells, including osteoblasts and Nestin<sup>+</sup> periarteriolar cells, several lines of histological and genetic evidence have demonstrated that the single population of mesenchymal stem cells, termed CXC chemokine ligand 12 (CXCL12)–abundant reticular (CAR) cells, which overlap strongly with leptin receptor–expressing (LepR<sup>+</sup>) cells, is the major cellular component of niches for hematopoietic stem cells (HSCs) and hematopoiesis in the bone marrow (BM). Expression of p16, a marker for senescent cells, and interleukin (IL)-1β and γH2AX foci, a marker for DNA damage, were increased in CAR/LepR<sup>+</sup> cells and osteoblasts with age. However, the most striking phenotype of aging in the human BM is yellow marrow, which consists predominantly of adipocytes, causing the decreased volume of the principal site of hematopoiesis probably with the decreased numbers of HSCs in the total body. BM adipocytes are derived from CAR/LepR<sup>+</sup> cells and act as negative or positive regulators of HSCs during homeostasis and myelosuppressive condition. Therefore, a fundamental question is how a portion of BM CAR/LepR<sup>+</sup> cells differentiate into adipocytes during aging. Many rounds of inflammatory stress induced yellow marrow in mice. On the other hand, type H vessels found in the metaphysis and peripheral nerves running along the arteries were markedly reduced in the marrow of aged mice, which might affect HSCs and/or their niche cells. Understanding the cellular and molecular function of aged HSC niches could enable pharmacological regulation of niche functions to facilitate control of disease caused by BM aging.</div></div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"144 ","pages":"Article 104749"},"PeriodicalIF":2.5,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143467483","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

In Memoriam: Prof. Vittorio Rizzoli, The visionary who built experimental hematology in Italy

IF 2.5 4区医学

Experimental hematology Pub Date : 2025-02-17 DOI: 10.1016/j.exphem.2025.104735

引用次数: 0

Preconditioning intervention prior to allogeneic hematopoietic stem cell transplantation in patients with high-risk acute myeloid leukemia

IF 2.5 4区医学

Experimental hematology Pub Date : 2025-02-12 DOI: 10.1016/j.exphem.2025.104746

Takayoshi Tachibana , Akihiko Izumi , Shota Arai , Takaaki Takeda , Natsuki Hirose , Yotaro Tamai , Shuku Sato , Chizuko Hashimoto , Katsumichi Fujimaki , Ryuji Ishii , Hirotaka Sakai , Etsuko Yamazaki , Yasuyuki Inoue , Masatsugu Tanaka , Hideaki Nakajima

{"title":"Preconditioning intervention prior to allogeneic hematopoietic stem cell transplantation in patients with high-risk acute myeloid leukemia","authors":"Takayoshi Tachibana , Akihiko Izumi , Shota Arai , Takaaki Takeda , Natsuki Hirose , Yotaro Tamai , Shuku Sato , Chizuko Hashimoto , Katsumichi Fujimaki , Ryuji Ishii , Hirotaka Sakai , Etsuko Yamazaki , Yasuyuki Inoue , Masatsugu Tanaka , Hideaki Nakajima","doi":"10.1016/j.exphem.2025.104746","DOIUrl":"10.1016/j.exphem.2025.104746","url":null,"abstract":"<div><div>The outcomes of patients with high-risk acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (HCT) remain poor despite many attempts at developing therapeutic strategies. Preconditioning interventions (PCIs) have been applied to patients with high-risk AML to reduce the disease burden before starting the conditioning regimen. A single-center retrospective study was performed to evaluate the safety and efficacy of PCI in allograft patients with high-risk AML. Thirty-three patients with a median age of 57 (16–70) years were included to the entire cohort. Among various PCI regimens, venetoclax plus azacitidine was administered to 12 patients. The median drug withdrawal day was 0 days (range, 0–12) for low-intensity PCIs and 12 days (range, 8–14) for high-intensity PCIs. With no grade 3 nonhematological adverse events during PCIs, the median blast fraction in the bone marrow before and after PCIs decreased from 12.4% to 2.1% (<em>p</em> = 0.001). Excluding three patients with early complication-related deaths, all 30 patients achieved engraftment within a median of 30 days. The overall survival, cumulative incidence of relapse, and nonrelapse mortality (NRM) rates at 2 years were 67.1%, 23.9%, and 8.8%, respectively. The cumulative incidences of grade II–IV acute graft-versus-host disease (GVHD) at 100 days and chronic GVHD at 2 years were 32.4% and 23.5%, respectively. PCI may be safe and effective in promoting engraftment and reducing the risk of disease relapse without increasing the risk of NRM. Further clinical trials are warranted to establish appropriate PCI strategies.</div></div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"144 ","pages":"Article 104746"},"PeriodicalIF":2.5,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143425392","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

Charting new paths in experimental hematology: Revitalizing the editorial board and upcoming initiatives

IF 2.5 4区医学

Experimental hematology Pub Date : 2025-02-11 DOI: 10.1016/j.exphem.2025.104745

Keisuke Ito

引用次数: 0

CBX7 inhibitors affect H3K9 methyltransferase-regulated gene repression in leukemic cells CBX7抑制剂影响白血病细胞中H3K9甲基转移酶调节的基因抑制。

IF 2.5 4区医学

Experimental hematology Pub Date : 2025-02-01 DOI: 10.1016/j.exphem.2024.104691

Anne P. de Groot , Huong Nguyen , Jacobine S. Pouw , Ellen Weersing , Albertina Dethmers-Ausema , Gerald de Haan

{"title":"CBX7 inhibitors affect H3K9 methyltransferase-regulated gene repression in leukemic cells","authors":"Anne P. de Groot , Huong Nguyen , Jacobine S. Pouw , Ellen Weersing , Albertina Dethmers-Ausema , Gerald de Haan","doi":"10.1016/j.exphem.2024.104691","DOIUrl":"10.1016/j.exphem.2024.104691","url":null,"abstract":"<div><div>The epigenome of leukemic cells is dysregulated, and genes required for cell cycle arrest and differentiation may become repressed, which contributes to the accumulation of undifferentiated malignant blood cells. Here, we show that the Polycomb group protein CBX7 can interact with H3K9 methyltransferases EHMT1/2 and SETDB1. We aimed to assess whether combined interfering with these H3K9 methyltransferases and CBX7 could derepress target genes and thereby induce growth arrest of leukemic cells. We found that pharmacologic inhibition of CBX7 abolishes the interaction of CBX7 with EHMT1/2 and SETDB1 and subsequently reduces H3K9 methylation levels which reactivates target gene expression. Reversely, upon pharmacologic inhibition of H3K9 methyltransferases, CBX7 can take over gene repression. Finally, we found that combined inhibition of CBX7 and EHMT1/2 or SETDB1 had additive effects on reducing cell growth and inducing differentiation. However, we did not detect changes in epigenetic modifications, nor target gene derepression, after combination treatment. In contrast, CBX7 inhibitors alone did affect both Polycomb-associated H2Aub-mediated gene repression as well as H3K9 methyltransferase activity. Therefore, we suggest that CBX7 is a promising therapeutic target in leukemia, as its inhibition can reactivate Polycomb and H3K9 methyltransferase target gene expression.</div></div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"142 ","pages":"Article 104691"},"PeriodicalIF":2.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142754804","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

KLF4 enhances transplantation-induced hematopoiesis by inhibiting TLRs and noncanonical NFκB signaling at a steady state

IF 2.5 4区医学

Experimental hematology Pub Date : 2025-02-01 DOI: 10.1016/j.exphem.2025.104730

Chun Shik Park , Cory S. Bridges , Andrew H. Lewis , Taylor J. Chen , Saptarsi Shai , Wa Du , Monica Puppi , Barry Zorman , Sumazin Pavel , H. Daniel Lacorazza

{"title":"KLF4 enhances transplantation-induced hematopoiesis by inhibiting TLRs and noncanonical NFκB signaling at a steady state","authors":"Chun Shik Park , Cory S. Bridges , Andrew H. Lewis , Taylor J. Chen , Saptarsi Shai , Wa Du , Monica Puppi , Barry Zorman , Sumazin Pavel , H. Daniel Lacorazza","doi":"10.1016/j.exphem.2025.104730","DOIUrl":"10.1016/j.exphem.2025.104730","url":null,"abstract":"<div><div>The transcription factor Krüppel-like factor 4 (KLF4) acts as a transcriptional activator and repressor. KLF4 plays a role in various cellular processes, including the dedifferentiation of somatic cells into induced pluripotent stem cells. Although it has been shown to enhance self-renewal in embryonic and leukemia stem cells, its role in adult hematopoietic stem cells (HSCs) remains underexplored. We demonstrate that conditional deletion of the <em>Klf4</em> gene in hematopoietic cells led to an increased frequency of immunophenotypic HSCs in the bone marrow, along with a normal distribution of lymphoid and myeloid progenitor cells. Noncompetitive bone marrow transplants showed normal engraftment and multilineage reconstitution, except for monocytes and T cells. However, the loss of KLF4 hindered hematologic reconstitution in competitive serial bone marrow transplants, highlighting a critical role for KLF4 in stress-induced hematopoiesis. Transcriptome analysis revealed an upregulation of NFκB2 and toll-like receptors (e.g., TLR4) in Klf4-null HSCs during homeostasis. Flow cytometry and immunoblot analysis confirmed the increased cell surface expression of TLR4 and the activation of NFκB2 in HSCs under homeostatic conditions, whereas NF<em>κ</em>B2 expression drops after radiation compared with steady-state levels. Our findings suggest that the constitutive activation of the TLR4–NFκB2 pathway inhibits the ability of HSCs to regenerate blood after transplantation in cytoablated bone marrow.</div></div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"144 ","pages":"Article 104730"},"PeriodicalIF":2.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143122536","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

Nucleic acid metabolism: the key therapeutic target for myeloid tumors 核酸代谢：髓系肿瘤的关键治疗靶点。

IF 2.5 4区医学

Experimental hematology Pub Date : 2025-02-01 DOI: 10.1016/j.exphem.2024.104693

Tomohiro Yabushita , Susumu Goyama

引用次数: 0

The developmental clock: where art and science meet 发育时钟：艺术与科学交汇的地方。

IF 2.5 4区医学

Experimental hematology Pub Date : 2025-02-01 DOI: 10.1016/j.exphem.2024.104695

John D. Crispino

引用次数: 0