Pub Date : 2025-12-13DOI: 10.1016/j.exphem.2025.105352
Miguel Ganuza , Momoko Yoshimoto
Recent advances in developmental hematology have revealed unappreciated hematopoietic waves and origins during development, and unexpected hematopoietic stem cell (HSC)-independent progenitors that provide lifelong hematopoiesis, using in vivo barcoding technologies and various lineage-tracing mouse models. Also, these tools estimate HSC numbers and display HSC behaviors that have not been anticipated. This review introduces such new discoveries in blood development and discusses the data and controversies.
{"title":"Hematopoietic stem cell-independent and -dependent hematopoiesis: new insights and lineage-tracing methods","authors":"Miguel Ganuza , Momoko Yoshimoto","doi":"10.1016/j.exphem.2025.105352","DOIUrl":"10.1016/j.exphem.2025.105352","url":null,"abstract":"<div><div>Recent advances in developmental hematology have revealed unappreciated hematopoietic waves and origins during development, and unexpected hematopoietic stem cell (HSC)-independent progenitors that provide lifelong hematopoiesis, using in vivo barcoding technologies and various lineage-tracing mouse models. Also, these tools estimate HSC numbers and display HSC behaviors that have not been anticipated. This review introduces such new discoveries in blood development and discusses the data and controversies.</div></div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"155 ","pages":"Article 105352"},"PeriodicalIF":2.1,"publicationDate":"2025-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145762611","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}
Pub Date : 2025-12-08DOI: 10.1016/j.exphem.2025.105347
Alasdair Duguid , Camille Malouf , Leslie Nitsche , Christina Halsey , Katrin Ottersbach
KMT2A-rearranged (KMT2A-r) infant leukemia can present as a lymphoid, myeloid, or mixed-lineage leukemia and frequently involves the central nervous system (CNS); yet, the impact of this lineage diversity and plasticity on CNS involvement remains poorly understood. Using a fully murine immunocompetent model of KMT2A-AFF1+ mixed-lineage infant leukemia, we investigated how the CNS niche influences the phenotype and function of leukemia propagating cells (LPCs). Previously defined bone marrow (BM)–derived LPCs were transplanted and shown to engraft the CNS, although not equally; lineage-negative cKit+ common lymphoid progenitor cells were consistently underrepresented in the niche. Transplants of CNS-derived LPCs, modelling relapse, demonstrated reduced systemic repopulation capacity, with many recipients exhibiting stable long-term engraftment without developing overt leukemia, a phenomenon not observed in BM-derived transplants. Transcriptomic profiling of matched CNS- and BM-derived LPCs revealed enrichment of pathways involved in hypoxia, lipid and cholesterol homeostasis, and inflammatory signaling in the CNS. Notably, LPC subsets that successfully adapted to the CNS niche upregulated lipid and fatty acid metabolic programs. CNS-derived LPCs showed increased expression of genes involved in T cell immune modulation, suggesting a skew to a more immunosuppressive environment. These findings indicate that the CNS niche imposes selective pressures that cause lasting metabolic and functional reprogramming of leukemic cells, impairing their ability to reestablish systemic disease and potentially affecting immune cell interactions. Furthermore, these findings may be more generally relevant to primary mixed-lineage infant leukemia and, increasingly important, lineage-switched infant leukemia.
{"title":"Mixed-lineage leukemia cells undergo unique adaptations in the CNS niche","authors":"Alasdair Duguid , Camille Malouf , Leslie Nitsche , Christina Halsey , Katrin Ottersbach","doi":"10.1016/j.exphem.2025.105347","DOIUrl":"10.1016/j.exphem.2025.105347","url":null,"abstract":"<div><div>KMT2A-rearranged (KMT2A-r) infant leukemia can present as a lymphoid, myeloid, or mixed-lineage leukemia and frequently involves the central nervous system (CNS); yet, the impact of this lineage diversity and plasticity on CNS involvement remains poorly understood. Using a fully murine immunocompetent model of KMT2A-AFF1+ mixed-lineage infant leukemia, we investigated how the CNS niche influences the phenotype and function of leukemia propagating cells (LPCs). Previously defined bone marrow (BM)–derived LPCs were transplanted and shown to engraft the CNS, although not equally; lineage-negative cKit+ common lymphoid progenitor cells were consistently underrepresented in the niche. Transplants of CNS-derived LPCs, modelling relapse, demonstrated reduced systemic repopulation capacity, with many recipients exhibiting stable long-term engraftment without developing overt leukemia, a phenomenon not observed in BM-derived transplants. Transcriptomic profiling of matched CNS- and BM-derived LPCs revealed enrichment of pathways involved in hypoxia, lipid and cholesterol homeostasis, and inflammatory signaling in the CNS. Notably, LPC subsets that successfully adapted to the CNS niche upregulated lipid and fatty acid metabolic programs. CNS-derived LPCs showed increased expression of genes involved in T cell immune modulation, suggesting a skew to a more immunosuppressive environment. These findings indicate that the CNS niche imposes selective pressures that cause lasting metabolic and functional reprogramming of leukemic cells, impairing their ability to reestablish systemic disease and potentially affecting immune cell interactions. Furthermore, these findings may be more generally relevant to primary mixed-lineage infant leukemia and, increasingly important, lineage-switched infant leukemia.</div></div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"154 ","pages":"Article 105347"},"PeriodicalIF":2.1,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145721936","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}
Pub Date : 2025-12-07DOI: 10.1016/j.exphem.2025.105346
Yumi Aoyama , Hiromi Yamazaki , Daichi Inoue
Selenoproteins—a unique class of antioxidant enzymes characterized by the incorporation of selenocysteine at their catalytic core—function as pivotal regulators of redox homeostasis in hematopoiesis. This review elucidates how selenoprotein-mediated redox control orchestrates hematopoietic stem cell (HSC) fate decisions, maintaining the critical balance between self-renewal and differentiation. The glutathione peroxidase (GPX) family, particularly GPX1 and GPX4, plays indispensable roles in hydrogen peroxide detoxification and protection against lipid peroxidation-induced ferroptotic cell death, respectively. Similarly, thioredoxin reductases (TXNRDs) sustain critical redox equilibrium via thioredoxin regeneration. Recent studies demonstrate that these redox regulators facilitate the proliferation and differentiation of HSCs and mature lineages. Selenoprotein deficiency disrupts HSC fitness, impairs B- and erythroid-lineage maturation, and induces B-to-myeloid lineage switching—pathogenic features observed in aged hematopoiesis, highlighting the critical roles of selenoproteins in balanced, healthy hematopoiesis. Emerging evidence demonstrates that leukemic cells also exploit selenoprotein pathways to mitigate oxidative stress, suggesting that selective modulation of specific selenoproteins may constitute a promising therapeutic approach, provided we delineate their differential utilization between normal and malignant hematopoiesis. Selenoproteins function at the intersection of several transcriptional networks, including NRF2, whose orchestrated antioxidant responses may alter during aging and malignant transformation. Indeed, selenoproteins possess unique properties and function with tissue-specific expression patterns and nonredundant or redundant functions across different hematopoietic lineages. Understanding the contribution of selenoproteins to hematopoietic regulation offers promising avenues for developing targeted therapeutic strategies in hematologic disorders and rejuvenating aged hematopoiesis, potentially through precision-guided modulation of selenoprotein-dependent pathways.
{"title":"Emerging paradigms in redox regulation: the role of selenoproteins in normal and malignant hematopoiesis","authors":"Yumi Aoyama , Hiromi Yamazaki , Daichi Inoue","doi":"10.1016/j.exphem.2025.105346","DOIUrl":"10.1016/j.exphem.2025.105346","url":null,"abstract":"<div><div>Selenoproteins—a unique class of antioxidant enzymes characterized by the incorporation of selenocysteine at their catalytic core—function as pivotal regulators of redox homeostasis in hematopoiesis. This review elucidates how selenoprotein-mediated redox control orchestrates hematopoietic stem cell (HSC) fate decisions, maintaining the critical balance between self-renewal and differentiation. The glutathione peroxidase (GPX) family, particularly GPX1 and GPX4, plays indispensable roles in hydrogen peroxide detoxification and protection against lipid peroxidation-induced ferroptotic cell death, respectively. Similarly, thioredoxin reductases (TXNRDs) sustain critical redox equilibrium via thioredoxin regeneration. Recent studies demonstrate that these redox regulators facilitate the proliferation and differentiation of HSCs and mature lineages. Selenoprotein deficiency disrupts HSC fitness, impairs B- and erythroid-lineage maturation, and induces B-to-myeloid lineage switching—pathogenic features observed in aged hematopoiesis, highlighting the critical roles of selenoproteins in balanced, healthy hematopoiesis. Emerging evidence demonstrates that leukemic cells also exploit selenoprotein pathways to mitigate oxidative stress, suggesting that selective modulation of specific selenoproteins may constitute a promising therapeutic approach, provided we delineate their differential utilization between normal and malignant hematopoiesis. Selenoproteins function at the intersection of several transcriptional networks, including NRF2, whose orchestrated antioxidant responses may alter during aging and malignant transformation. Indeed, selenoproteins possess unique properties and function with tissue-specific expression patterns and nonredundant or redundant functions across different hematopoietic lineages. Understanding the contribution of selenoproteins to hematopoietic regulation offers promising avenues for developing targeted therapeutic strategies in hematologic disorders and rejuvenating aged hematopoiesis, potentially through precision-guided modulation of selenoprotein-dependent pathways.</div></div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"155 ","pages":"Article 105346"},"PeriodicalIF":2.1,"publicationDate":"2025-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145713832","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}
Pub Date : 2025-12-06DOI: 10.1016/j.exphem.2025.105340
Conny K. Baldauf , Linda Poschmann , Bärbel Edelmann-Stephan , Frank Angenstein , Tobias R. Haage , Vikas Bhuria , Lars Philipsen , Hannes Berlin , Daniela C. Dieterich , Martin Böttcher , Dimitrios Mougiakakos , Burkhart Schraven , Thomas Fischer
The molecular mechanisms driving splenomegaly in myeloproliferative neoplasms (MPNs) remain poorly understood. Utilizing the Jak2-V617F knock-in mouse model, we investigated the role of β1- and β2-integrins in regulating spleen volume and spleen weight. The response to neutralizing antibodies against VLA-4 and the β2-integrin chain, as well as to isotype controls, was evaluated by serial intraindividual magnetic resonance imaging, by assessment of spleen weight and by analysis of the cellular composition of spleens. Short-term anti-VLA-4/β2-integrin treatment (applied on day 1 and evaluated at day 8) significantly reduced the spleen volume by 30% compared with the immunoglobulin G (IgG) control. At the cellular level, anti-integrin treatment led to a substantial 30% decrease in erythroblast counts and a 23% reduction in basophilic erythroblasts within the spleen, as compared with the isotype control. Furthermore, immunohistochemistry analysis of spleen sections revealed that CD71 (= Transferrin receptor protein 1) expression in spleen remained largely unchanged, whereas there was a clear reduction in Ter119 expression upon anti-integrin treatment. These data suggest that the substantial decrease in erythroblasts following anti-integrin treatment is a primary factor contributing to the overall reduction in spleen size. To study the spleen architecture, multiepitope ligand cartography (MELC) analysis of spleen sections was applied. This demonstrated that the spatial distribution of the marginal zone, red pulp, and white pulp remained unaltered upon anti-integrin treatment in JAK2-V617F knock-in mice. In summary, the present study identified a previously unrecognized role of the β1-integrin VLA-4 and of β2-integrin chains in extramedullary erythropoiesis of the spleen in JAK2-V617F-induced disease.
{"title":"Integrin-dependence of extramedullary erythropoiesis in the spleen of Jak2-V617F positive myeloproliferative neoplasm in mice","authors":"Conny K. Baldauf , Linda Poschmann , Bärbel Edelmann-Stephan , Frank Angenstein , Tobias R. Haage , Vikas Bhuria , Lars Philipsen , Hannes Berlin , Daniela C. Dieterich , Martin Böttcher , Dimitrios Mougiakakos , Burkhart Schraven , Thomas Fischer","doi":"10.1016/j.exphem.2025.105340","DOIUrl":"10.1016/j.exphem.2025.105340","url":null,"abstract":"<div><div>The molecular mechanisms driving splenomegaly in myeloproliferative neoplasms (MPNs) remain poorly understood. Utilizing the <em>Jak2-V617F</em> knock-in mouse model, we investigated the role of β1- and β2-integrins in regulating spleen volume and spleen weight. The response to neutralizing antibodies against VLA-4 and the β2-integrin chain, as well as to isotype controls, was evaluated by serial intraindividual magnetic resonance imaging, by assessment of spleen weight and by analysis of the cellular composition of spleens. Short-term anti-VLA-4/β2-integrin treatment (applied on day 1 and evaluated at day 8) significantly reduced the spleen volume by 30% compared with the immunoglobulin G (IgG) control. At the cellular level, anti-integrin treatment led to a substantial 30% decrease in erythroblast counts and a 23% reduction in basophilic erythroblasts within the spleen, as compared with the isotype control. Furthermore, immunohistochemistry analysis of spleen sections revealed that CD71 (= Transferrin receptor protein 1) expression in spleen remained largely unchanged, whereas there was a clear reduction in Ter119 expression upon anti-integrin treatment. These data suggest that the substantial decrease in erythroblasts following anti-integrin treatment is a primary factor contributing to the overall reduction in spleen size. To study the spleen architecture, multiepitope ligand cartography (MELC) analysis of spleen sections was applied. This demonstrated that the spatial distribution of the marginal zone, red pulp, and white pulp remained unaltered upon anti-integrin treatment in JAK2-V617F knock-in mice. In summary, the present study identified a previously unrecognized role of the β1-integrin VLA-4 and of β2-integrin chains in extramedullary erythropoiesis of the spleen in JAK2-V617F-induced disease.</div></div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"154 ","pages":"Article 105340"},"PeriodicalIF":2.1,"publicationDate":"2025-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145707878","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}
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.
{"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":"2025-12-04","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}
Pub Date : 2025-12-01DOI: 10.1016/j.exphem.2025.105334
Emma Bailey , Foteini Kalampalika , Raúl Sánchez-Lanzas , Justin Barclay , Amanda Jiménez-Pompa , Jun Wang , Miguel Ganuza
Over the recent years, pigs have re-emerged as an alternative source of organs for xenotransplantation into humans with the promise to overcome a worldwide shortage of human donors. Xenotransplantation still faces critical issues with immune rejection that could be potentially solved by the generation of lymphohematopoietic chimeras. Moreover, pig hematopoietic stem and progenitor cells (HSPCs) can constitute an unlimited source of HSPCs for lifesaving HSPC transplantation in bone marrow (BM) failure and after chemotherapy, among other cell therapies. The generation of these hematopoietic chimeras requires a profound study of pig hematopoiesis including pig HSPCs. Importantly, through single-cell RNA sequencing of pig BM cells we identified pig HSPC populations transcriptionally similar to those in humans and many common transcriptional regulators of hematopoiesis evolutionarily preserved in erythromyeloid and lymphoid differentiation. This supports that hematopoiesis in pigs is hierarchically organized and regulated in a very similar fashion as in humans. We also provided a sorting strategy for the identification and isolation of several putative pig HSPC populations, which should open a new means to functionally study pig hematopoiesis.
{"title":"Pig and human adult hematopoietic stem and progenitor cells are overall transcriptionally similar","authors":"Emma Bailey , Foteini Kalampalika , Raúl Sánchez-Lanzas , Justin Barclay , Amanda Jiménez-Pompa , Jun Wang , Miguel Ganuza","doi":"10.1016/j.exphem.2025.105334","DOIUrl":"10.1016/j.exphem.2025.105334","url":null,"abstract":"<div><div>Over the recent years, pigs have re-emerged as an alternative source of organs for xenotransplantation into humans with the promise to overcome a worldwide shortage of human donors. Xenotransplantation still faces critical issues with immune rejection that could be potentially solved by the generation of lymphohematopoietic chimeras. Moreover, pig hematopoietic stem and progenitor cells (HSPCs) can constitute an unlimited source of HSPCs for lifesaving HSPC transplantation in bone marrow (BM) failure and after chemotherapy, among other cell therapies. The generation of these hematopoietic chimeras requires a profound study of pig hematopoiesis including pig HSPCs. Importantly, through single-cell RNA sequencing of pig BM cells we identified pig HSPC populations transcriptionally similar to those in humans and many common transcriptional regulators of hematopoiesis evolutionarily preserved in erythromyeloid and lymphoid differentiation. This supports that hematopoiesis in pigs is hierarchically organized and regulated in a very similar fashion as in humans. We also provided a sorting strategy for the identification and isolation of several putative pig HSPC populations, which should open a new means to functionally study pig hematopoiesis.</div></div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"154 ","pages":"Article 105334"},"PeriodicalIF":2.1,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145667873","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}
We investigated the clinical significance of a rare germline SH2B3 variant (c.232G>A; p.Glu78Lys) identified by targeted next-generation sequencing (NGS) in patients with myeloproliferative neoplasms (MPNs). Among approximately 330 patients, three heterozygous carriers (≈1.0% prevalence) were identified by NGS and confirmed as germline (buccal swab) by Sanger sequencing. Two of the carriers presented with essential thrombocythemia that progressed to secondary myelofibrosis, and one presented with primary myelofibrosis that evolved to acute myeloid leukemia. The variant co-occurred with canonical somatic drivers (CALR or MPL) in the first two cases and with MPL plus additional somatic alterations (SRSF2, TET2) in the third. The p.Glu78Lys substitution localizes in the N-terminal dimerization domain of SH2B3. This germline variant is rare in population databases (allele frequency ∼1.1–2.2 per 1,000 inhabitants), and is currently classified as a variant of uncertain significance. In silico predictions were discordant, whereas structural modeling predicts disruption of critical hydrogen bonding at the dimer interface, suggesting potential functional impact. Although heterozygosity alone appears insufficient to drive disease, the enrichment of this variant in our MPN cohort and its occurrence in relatively young patients support a possible low-penetrance predisposition role. Functional assays, larger case–control series, and assessment of genetic/epigenetic modifiers are needed to define pathogenicity and clinical utility.
{"title":"Germline heterozygous SH2B3 p.Glu78Lys variant: a three-patient case series with myeloproliferative neoplasms","authors":"Giovanni Iaquinta , Alessandro Laganà , Anna Tamburini , Caterina Tatarelli , Patrizia Chiusolo , Elena Rossi , Monica Rossi , Michele Ragazzo , Emanuele Savino , Massimo Breccia , Paola Grammatico","doi":"10.1016/j.exphem.2025.105333","DOIUrl":"10.1016/j.exphem.2025.105333","url":null,"abstract":"<div><div>We investigated the clinical significance of a rare germline <em>SH2B3</em> variant (c.232G>A; p.Glu78Lys) identified by targeted next-generation sequencing (NGS) in patients with myeloproliferative neoplasms (MPNs). Among approximately 330 patients, three heterozygous carriers (≈1.0% prevalence) were identified by NGS and confirmed as germline (buccal swab) by Sanger sequencing. Two of the carriers presented with essential thrombocythemia that progressed to secondary myelofibrosis, and one presented with primary myelofibrosis that evolved to acute myeloid leukemia. The variant co-occurred with canonical somatic drivers (<em>CALR</em> or <em>MPL</em>) in the first two cases and with MPL plus additional somatic alterations (<em>SRSF2, TET2</em>) in the third. The p.Glu78Lys substitution localizes in the N-terminal dimerization domain of <em>SH2B3</em>. This germline variant is rare in population databases (allele frequency ∼1.1–2.2 per 1,000 inhabitants), and is currently classified as a variant of uncertain significance. In silico predictions were discordant, whereas structural modeling predicts disruption of critical hydrogen bonding at the dimer interface, suggesting potential functional impact. Although heterozygosity alone appears insufficient to drive disease, the enrichment of this variant in our MPN cohort and its occurrence in relatively young patients support a possible low-penetrance predisposition role. Functional assays, larger case–control series, and assessment of genetic/epigenetic modifiers are needed to define pathogenicity and clinical utility.</div></div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"154 ","pages":"Article 105333"},"PeriodicalIF":2.1,"publicationDate":"2025-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145654154","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}
Pub Date : 2025-11-28DOI: 10.1016/j.exphem.2025.105330
Rajdeep Roy , Tamalika Paul , Pritam Kumar Das , Samraj Sinha , Siddhartha Sankar Ray , Maitreyee Bhattacharyya , Nabendu Biswas
Drug resistance remains a critical barrier in effective cancer therapy. Previously, we demonstrated that expression of antiapoptotic protein (X‐linked inhibitor of apoptosis protein [XIAP]), contributes to the development of TRAIL resistance in chronic myeloid leukemia (CML) cells. However, upon acquiring drug resistance (K562R and KCL22R), XIAP degradation shifted from the lysosomal to the proteasomal pathway. Consistently, XIAP expression was markedly elevated in tumor samples compared with normal controls and was significantly higher in patients with an imatinib failure (IMA-FL) than in their counterparts who were imatinib responsive (IMA-RP) within the patient cohort. Moreover, we have found that proteasomal activity increased in imatinib-resistant cells and lysosomal pathway is inhibited. Mechanistically, we found that H₂O₂-induced activation of the ERK-mTOR axis suppressed autophagy in resistant cells, facilitating this shift in degradation pathway. Interestingly, dual intervention by restoring autophagic flux via mTOR inhibition and inducing XIAP degradation using H2O2 reverted imatinib resistance in K562R cells. Thus, our findings uncover a novel ERK–mTOR–axis for upregulation of proteasomal degradation of XIAP, which could be targeted to overcome imatinib resistance by combinatorial inhibition of mTOR and XIAP in CML. This study holds the promise of a new therapeutic strategy for overcoming drug resistance in cancer.
{"title":"ERK-mTOR crosstalk suppresses autophagy and upregulates proteasomal degradation pathway to confer chronic myeloid leukemia cells resistant to imatinib","authors":"Rajdeep Roy , Tamalika Paul , Pritam Kumar Das , Samraj Sinha , Siddhartha Sankar Ray , Maitreyee Bhattacharyya , Nabendu Biswas","doi":"10.1016/j.exphem.2025.105330","DOIUrl":"10.1016/j.exphem.2025.105330","url":null,"abstract":"<div><div>Drug resistance remains a critical barrier in effective cancer therapy. Previously, we demonstrated that expression of antiapoptotic protein (X‐linked inhibitor of apoptosis protein [XIAP]), contributes to the development of TRAIL resistance in chronic myeloid leukemia (CML) cells. However, upon acquiring drug resistance (K562R and KCL22R), XIAP degradation shifted from the lysosomal to the proteasomal pathway. Consistently, XIAP expression was markedly elevated in tumor samples compared with normal controls and was significantly higher in patients with an imatinib failure (IMA-FL) than in their counterparts who were imatinib responsive (IMA-RP) within the patient cohort. Moreover, we have found that proteasomal activity increased in imatinib-resistant cells and lysosomal pathway is inhibited. Mechanistically, we found that H₂O₂-induced activation of the ERK-mTOR axis suppressed autophagy in resistant cells, facilitating this shift in degradation pathway. Interestingly, dual intervention by restoring autophagic flux via mTOR inhibition and inducing XIAP degradation using H<sub>2</sub>O<sub>2</sub> reverted imatinib resistance in K562R cells. Thus, our findings uncover a novel ERK–mTOR–axis for upregulation of proteasomal degradation of XIAP, which could be targeted to overcome imatinib resistance by combinatorial inhibition of mTOR and XIAP in CML. This study holds the promise of a new therapeutic strategy for overcoming drug resistance in cancer.</div></div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"154 ","pages":"Article 105330"},"PeriodicalIF":2.1,"publicationDate":"2025-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145647657","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}
Pub Date : 2025-11-19DOI: 10.1016/j.exphem.2025.105327
Ling Ling , Jiawen Huang , Zhichen Dai , Lan Yang , Fan Yang , Fangyu Gong , Xinhui Qiu , Mengying Lv , Fangfang Wang , Jingyan Liang , Sheng He , Duonan Yu
The 3′ untranslated region (3′UTR) of mRNA is crucial for post-transcriptional gene regulation, primarily through miRNAs. However, the overall role of the Gata1 3′UTR in mammals remains unclear. In this study, we knocked out the Gata1 3′UTR and observed a defect in erythropoiesis in mutant mice, evidenced by macrocytic anemia at baseline. The deletion of the Gata1 3′UTR also caused deficiencies in erythropoiesis within fetal livers. Mechanistically, removing the Gata1 3′UTR destabilizes Gata1 mRNA, leading to decreased levels of Gata1 protein. This reduced stability results from the dissociation of AU-rich elements in the 3′UTR from a trans-acting factor called ELAV-like family 1 (ELAVL1). Specifically, we conducted an RNA pulldown assay followed by mass spectrometry to identify proteins that bind to the Gata1 3′UTR. Gene Ontology analysis revealed that Elavl1 is a binding partner across nearly all categories related to mRNA stabilization. Western blotting, RNA immunoprecipitation, and mutagenesis assays confirmed the direct interaction between the Gata1 3′UTR and Elavl1. Modulating Elavl1 activity or protein levels with the small molecule inhibitor dihydro-tanshinone-I, or through ectopic expression in erythroid cells, validated Elavl1 as a stabilizing factor for Gata1 mRNA. Our results highlight the important role of the Gata1 mRNA 3′UTR in erythroid development.
{"title":"Mouse Gata1 3′UTR modulates Gata1 levels to affect erythropoiesis","authors":"Ling Ling , Jiawen Huang , Zhichen Dai , Lan Yang , Fan Yang , Fangyu Gong , Xinhui Qiu , Mengying Lv , Fangfang Wang , Jingyan Liang , Sheng He , Duonan Yu","doi":"10.1016/j.exphem.2025.105327","DOIUrl":"10.1016/j.exphem.2025.105327","url":null,"abstract":"<div><div>The 3<em>′</em> untranslated region (<em>3′UTR</em>) of mRNA is crucial for post-transcriptional gene regulation, primarily through miRNAs. However, the overall role of the <em>Gata1 3′UTR</em> in mammals remains unclear. In this study, we knocked out the <em>Gata1 3′UTR</em> and observed a defect in erythropoiesis in mutant mice, evidenced by macrocytic anemia at baseline. The deletion of the <em>Gata1 3′UTR</em> also caused deficiencies in erythropoiesis within fetal livers. Mechanistically, removing the <em>Gata1 3′UTR</em> destabilizes <em>Gata1</em> mRNA, leading to decreased levels of Gata1 protein. This reduced stability results from the dissociation of AU-rich elements in the <em>3′UTR</em> from a trans-acting factor called ELAV-like family 1 (ELAVL1). Specifically, we conducted an RNA pulldown assay followed by mass spectrometry to identify proteins that bind to the <em>Gata1 3′UTR</em>. Gene Ontology analysis revealed that Elavl1 is a binding partner across nearly all categories related to mRNA stabilization. Western blotting, RNA immunoprecipitation, and mutagenesis assays confirmed the direct interaction between the <em>Gata1 3′UTR</em> and Elavl1. Modulating Elavl1 activity or protein levels with the small molecule inhibitor dihydro-tanshinone-I, or through ectopic expression in erythroid cells, validated Elavl1 as a stabilizing factor for <em>Gata1</em> mRNA. Our results highlight the important role of the <em>Gata1</em> mRNA 3<em>′</em>UTR in erythroid development.</div></div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"154 ","pages":"Article 105327"},"PeriodicalIF":2.1,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145573460","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}
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