Pub Date : 2026-02-01Epub 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":"2026-02-01","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 : 2026-02-01Epub Date: 2025-11-19DOI: 10.1016/j.exphem.2025.105326
Kavita Bisht, Valérie Barbier, Svetlana Shatunova, Ingrid G. Winkler, Jean-Pierre Lévesque
Stem cell antigen-1 (SCA1) is widely used to identify mouse hematopoietic stem cells (HSCs) and multipotent progenitors (MPPs) among lineage-negative KIT+ (LK) cells. However, SCA1 is expressed only in a few inbred mouse strains and becomes strongly upregulated in LK cells following in vivo challenge with interferons, lipopolysaccharide (LPS), or pathogens, leading to incorrect analysis of HSC functional subsets and delineation of HSC, MPP, and lineage-restricted progenitor phenotypes. Endothelial protein C receptor CD201 can be used as an alternative marker for mouse and even human HSC. However, whether CD201 expression changes following infectious challenge is unknown. Unlike SCA1, CD201 expression did not change on mouse LK cells in response to LPS in vivo. Long-term competitive transplantations with CD201+, CD201−, or SCA1+ LK cells showed that most reconstituting HSCs are within the LK CD201+ population after LPS challenge. However, the long-term competitive repopulation potential of LK SCA1+ cells from LPS-treated mice was much more severely reduced than that of LK CD201+ cells from the same LPS-treated donors, suggesting that the LK SCA1+ population in challenged donors becomes contaminated with CD201− progenitors devoid of long-term repopulation potential. Based on the CD201 gating strategy, we reassessed the effect of LPS on HSC and MPP cycling and mobilization and their dependency on MY88 and TRIF adaptors. In conclusion, CD201 enables a more accurate analysis of mouse HSC and MPP subsets in all inbred strains in septic conditions or steady state.
{"title":"Endothelial protein C receptor CD201 is a better marker than stem cell antigen-1 to identify mouse long-term reconstituting hematopoietic stem cells following septic challenge","authors":"Kavita Bisht, Valérie Barbier, Svetlana Shatunova, Ingrid G. Winkler, Jean-Pierre Lévesque","doi":"10.1016/j.exphem.2025.105326","DOIUrl":"10.1016/j.exphem.2025.105326","url":null,"abstract":"<div><div>Stem cell antigen-1 (SCA1) is widely used to identify mouse hematopoietic stem cells (HSCs) and multipotent progenitors (MPPs) among lineage-negative KIT<sup>+</sup> (LK) cells. However, SCA1 is expressed only in a few inbred mouse strains and becomes strongly upregulated in LK cells following in vivo challenge with interferons, lipopolysaccharide (LPS), or pathogens, leading to incorrect analysis of HSC functional subsets and delineation of HSC, MPP, and lineage-restricted progenitor phenotypes. Endothelial protein C receptor CD201 can be used as an alternative marker for mouse and even human HSC. However, whether CD201 expression changes following infectious challenge is unknown. Unlike SCA1, CD201 expression did not change on mouse LK cells in response to LPS in vivo. Long-term competitive transplantations with CD201<sup>+</sup>, CD201<sup>−</sup>, or SCA1<sup>+</sup> LK cells showed that most reconstituting HSCs are within the LK CD201<sup>+</sup> population after LPS challenge. However, the long-term competitive repopulation potential of LK SCA1<sup>+</sup> cells from LPS-treated mice was much more severely reduced than that of LK CD201<sup>+</sup> cells from the same LPS-treated donors, suggesting that the LK SCA1<sup>+</sup> population in challenged donors becomes contaminated with CD201<sup>−</sup> progenitors devoid of long-term repopulation potential. Based on the CD201 gating strategy, we reassessed the effect of LPS on HSC and MPP cycling and mobilization and their dependency on MY88 and TRIF adaptors. In conclusion, CD201 enables a more accurate analysis of mouse HSC and MPP subsets in all inbred strains in septic conditions or steady state.</div></div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"154 ","pages":"Article 105326"},"PeriodicalIF":2.1,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145573449","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 : 2026-01-31DOI: 10.1016/j.exphem.2026.105385
Shawn David, Griffin J Nye, Elizabeth Eudy, Ewelina Bolcun-Filas, Jennifer J Trowbridge, Kira A Young
Total body irradiation is routinely used for myeloablation before a mouse hematopoietic cell transplant. Widespread transition from 137Cs γ irradiators to x-ray systems has raised questions about whether these modalities yield equivalent biological outcomes. Although prior studies compared γ and x-ray irradiation in syngeneic transplants, their performance in reciprocal congenic models and in primary acute myeloid leukemia (AML) transplants remains unclear. Here, we systematically evaluated γ and x-ray irradiation across dose conditions and tested dose equivalents in CD45.1/CD45.2 reciprocal transplants and in AML transplant models. Although each modality exhibited distinct early effects, both ultimately supported comparable long-term donor peripheral blood (PB) chimerism in congenic transplants and equivalent AML engraftment, leukemic burden, and disease progression. These findings indicated that, with proper dose calibration, x-ray irradiation is a functionally effective alternative to γ irradiation for normal and malignant transplant studies.
{"title":"Functional equivalence of γ- and x-ray irradiation for long-term peripheral blood chimerism and acute myeloid leukemia transplant outcomes in mice.","authors":"Shawn David, Griffin J Nye, Elizabeth Eudy, Ewelina Bolcun-Filas, Jennifer J Trowbridge, Kira A Young","doi":"10.1016/j.exphem.2026.105385","DOIUrl":"10.1016/j.exphem.2026.105385","url":null,"abstract":"<p><p>Total body irradiation is routinely used for myeloablation before a mouse hematopoietic cell transplant. Widespread transition from <sup>137</sup>Cs γ irradiators to x-ray systems has raised questions about whether these modalities yield equivalent biological outcomes. Although prior studies compared γ and x-ray irradiation in syngeneic transplants, their performance in reciprocal congenic models and in primary acute myeloid leukemia (AML) transplants remains unclear. Here, we systematically evaluated γ and x-ray irradiation across dose conditions and tested dose equivalents in CD45.1/CD45.2 reciprocal transplants and in AML transplant models. Although each modality exhibited distinct early effects, both ultimately supported comparable long-term donor peripheral blood (PB) chimerism in congenic transplants and equivalent AML engraftment, leukemic burden, and disease progression. These findings indicated that, with proper dose calibration, x-ray irradiation is a functionally effective alternative to γ irradiation for normal and malignant transplant studies.</p>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":" ","pages":"105385"},"PeriodicalIF":2.1,"publicationDate":"2026-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146104196","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 : 2026-01-01Epub Date: 2025-09-28DOI: 10.1016/j.exphem.2025.105268
Leila Mahdavi , Fatemeh Alikarami , Haley Goodrow , Alexandra Lenard , Simone S. Riedel , Clara Libbrecht , Isabel Bowser , Sarah K. Tasian , Catherine D. Falkenstein , Bryan Manning , Sarah Skuli , Martin P. Carroll , Gerald Wertheim , Sheng F. Cai , Gerard McGeehan , Sixiang Yu , Junwei Shi , Hongbo M. Xie , Kathrin M. Bernt
Inhibitors of the menin-KMT2A interaction are promising agents for the treatment of KMT2A-rearranged leukemias. We evaluated menin inhibition in patient-derived xenografts of KMT2A-rearranged leukemias with high-risk features. Three acute myeloid leukemias with high-risk fusion partners (mixed-lineage leukemia-10 [MLLT10] and mixed-lineage leukemia-4 [MLLT4]) and two infant acute lymphocytic leukemia (ALL) samples were sensitive to menin inhibition. We also evaluated serial samples from two patients with multiply relapsed ALL. We found that highly pretreated KMT2A::AFF1 ALL samples were much less sensitive compared with cells obtained earlier in the same patients’ disease course. Because none of the patients had been treated with a menin inhibitor, resistance in these highly pretreated samples was acquired in the absence of menin-inhibitor exposure. Transcriptomic analysis documented sustained on-target efficacy toward the canonical targets of the menin inhibitor in resistant cells. Targeted genomic analysis documented the emergence of multiple comutations, including RAS pathway and TP53 mutations, although neither was sufficient to induce menin-inhibitor resistance in vitro. Downregulation of KMT3D may account for resistance in one patient; inactivation of KMT2C/D has been reported to result in menin-inhibitor resistance, and KMT2C-edited cells from this patient were selected for in menin-inhibitor–containing growth conditions. Future studies will need to clarify more broadly which genomic/epigenomic alterations drive upfront resistance. Regardless of mechanism, our data support using menin inhibitors upfront or in early lines of therapy before substantial genomic or epigenomic evolution has occurred.
{"title":"Upfront menin-inhibitor resistance in multiply pretreated leukemias","authors":"Leila Mahdavi , Fatemeh Alikarami , Haley Goodrow , Alexandra Lenard , Simone S. Riedel , Clara Libbrecht , Isabel Bowser , Sarah K. Tasian , Catherine D. Falkenstein , Bryan Manning , Sarah Skuli , Martin P. Carroll , Gerald Wertheim , Sheng F. Cai , Gerard McGeehan , Sixiang Yu , Junwei Shi , Hongbo M. Xie , Kathrin M. Bernt","doi":"10.1016/j.exphem.2025.105268","DOIUrl":"10.1016/j.exphem.2025.105268","url":null,"abstract":"<div><div>Inhibitors of the menin-KMT2A interaction are promising agents for the treatment of <em>KMT2A</em>-rearranged leukemias. We evaluated menin inhibition in patient-derived xenografts of <em>KMT2A</em>-rearranged leukemias with high-risk features. Three acute myeloid leukemias with high-risk fusion partners (mixed-lineage leukemia-10 [<em>MLLT10</em>] and mixed-lineage leukemia-4 [<em>MLLT4</em>]) and two infant acute lymphocytic leukemia (ALL) samples were sensitive to menin inhibition. We also evaluated serial samples from two patients with multiply relapsed ALL. We found that highly pretreated <em>KMT2A::AFF1</em> ALL samples were much less sensitive compared with cells obtained earlier in the same patients’ disease course. Because none of the patients had been treated with a menin inhibitor, resistance in these highly pretreated samples was acquired in the absence of menin-inhibitor exposure. Transcriptomic analysis documented sustained on-target efficacy toward the canonical targets of the menin inhibitor in resistant cells. Targeted genomic analysis documented the emergence of multiple comutations, including RAS pathway and <em>TP53</em> mutations, although neither was sufficient to induce menin-inhibitor resistance in vitro. Downregulation of KMT3D may account for resistance in one patient; inactivation of <em>KMT2C/D</em> has been reported to result in menin-inhibitor resistance, and <em>KMT2C-</em>edited cells from this patient were selected for in menin-inhibitor–containing growth conditions. Future studies will need to clarify more broadly which genomic/epigenomic alterations drive upfront resistance. Regardless of mechanism, our data support using menin inhibitors upfront or in early lines of therapy before substantial genomic or epigenomic evolution has occurred.</div></div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"153 ","pages":"Article 105268"},"PeriodicalIF":2.1,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145198910","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 : 2026-01-01Epub Date: 2025-11-07DOI: 10.1016/j.exphem.2025.105288
Adela S. Cellucci , Danila B. Yañuk , Paola R. Lev , Ana C. Glembotsky , Nora P. Goette , María C. Lira , Geraldine De Luca , Laureano J. Kamiya , Paula G. Heller , Rosana F. Marta
Cytoreductive treatment is a main strategy to reduce thrombotic complications and ameliorate symptoms in Phi-negative myeloproliferative neoplasms (MPNs) comprising essential thrombocythemia, polycythemia vera, and primary myelofibrosis. Based on the observation of differences in platelet size during microscopic analysis of blood smears from MPN patients, in this work we studied whether these differences could be dependent on the type of cytoreductive drug used for patients’ treatment and whether changes in platelet size could be induced by the effect of these drugs on thrombopoiesis. Maximum platelet diameter (MPD) was measured in 120 patients with MPN. The effect of drugs on thrombopoiesis was evaluated in normal megakaryocytes (MKs) obtained from cord blood–derived CD34+ hematopoietic progenitors. Anagrelide (ANA), α-interferon (IFN), and ruxolitinib (Ruxo) increased, whereas hydroxyurea (HU) decreased platelet size. MK incubation with these drugs revealed that ANA and IFN induced abnormal proplatelet (PP) architecture and affected microtubular structure, but only ANA altered actin organization, whereas neither Ruxo nor HU modified MK cytoskeleton. By bioinformatic analysis, RANTES downregulation was identified as a candidate responsible for ANA-induced abnormalities. RANTES downregulation was confirmed in MK incubated with ANA but not with IFN. Addition of recombinant RANTES reverted ANA-induced cytoskeletal abnormalities. Evaluation of RANTES plasmatic levels and platelet RNA expression in patients with MPN showed RANTES decrease in both samples during ANA treatment, suggesting that in vitro findings could reflect ANA action in vivo. In conclusion, this study demonstrates the influence of cytoreductive drugs on platelet size and reveals their differential mechanisms of action during platelet production.
{"title":"Cytoreductive treatment differentially affects platelet size and cytoskeletal megakaryocyte organization during thrombopoiesis in myeloproliferative neoplasms","authors":"Adela S. Cellucci , Danila B. Yañuk , Paola R. Lev , Ana C. Glembotsky , Nora P. Goette , María C. Lira , Geraldine De Luca , Laureano J. Kamiya , Paula G. Heller , Rosana F. Marta","doi":"10.1016/j.exphem.2025.105288","DOIUrl":"10.1016/j.exphem.2025.105288","url":null,"abstract":"<div><div>Cytoreductive treatment is a main strategy to reduce thrombotic complications and ameliorate symptoms in Phi-negative myeloproliferative neoplasms (MPNs) comprising essential thrombocythemia, polycythemia vera, and primary myelofibrosis. Based on the observation of differences in platelet size during microscopic analysis of blood smears from MPN patients, in this work we studied whether these differences could be dependent on the type of cytoreductive drug used for patients’ treatment and whether changes in platelet size could be induced by the effect of these drugs on thrombopoiesis. Maximum platelet diameter (MPD) was measured in 120 patients with MPN. The effect of drugs on thrombopoiesis was evaluated in normal megakaryocytes (MKs) obtained from cord blood–derived CD34+ hematopoietic progenitors. Anagrelide (ANA), α-interferon (IFN), and ruxolitinib (Ruxo) increased, whereas hydroxyurea (HU) decreased platelet size. MK incubation with these drugs revealed that ANA and IFN induced abnormal proplatelet (PP) architecture and affected microtubular structure, but only ANA altered actin organization, whereas neither Ruxo nor HU modified MK cytoskeleton. By bioinformatic analysis, RANTES downregulation was identified as a candidate responsible for ANA-induced abnormalities. RANTES downregulation was confirmed in MK incubated with ANA but not with IFN. Addition of recombinant RANTES reverted ANA-induced cytoskeletal abnormalities. Evaluation of RANTES plasmatic levels and platelet RNA expression in patients with MPN showed RANTES decrease in both samples during ANA treatment, suggesting that <em>in vitro</em> findings could reflect ANA action <em>in vivo</em>. In conclusion, this study demonstrates the influence of cytoreductive drugs on platelet size and reveals their differential mechanisms of action during platelet production.</div></div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"153 ","pages":"Article 105288"},"PeriodicalIF":2.1,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145476589","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 : 2026-01-01Epub Date: 2025-10-30DOI: 10.1016/j.exphem.2025.105287
Shannon E. Conneely , Alexis Quezada , Kristen J. Kurtz , Nenggang Zhang , Josephine De La Fuente , Nesa Mercer , Jason H. Rogers , Rogelio Aguilar , Geraldo Medrano , Margaret A. Goodell , Paul P. Liu , Debananda Pati , Rachel E. Rau
Cohesin gene mutations occur in many malignancies, including acute myeloid leukemia (AML). Loss-of-function mutations in the four major cohesin complex genes (RAD21, SMC3, SMC1a, and STAG2) occur across most major genetic subtypes of AML but are notably absent in AML harboring CBFB::MYH11, suggesting that cohesin mutations yield distinct biological outcomes dependent on the genetic AML driver. We hypothesized that CBFB::MYH11-expressing leukemias would be dependent on intact cohesin genes given their near-mutual exclusivity. To investigate this, we combined either germline or inducible heterozygous deletions in cohesin genes Smc3 or Rad21, respectively, with an inducible murine model of Cbfb::MYH11 AML. This approach allowed us to evaluate the effects of cohesin haploinsufficiency on leukemia development, chromatin accessibility, and transcriptional output. We demonstrated that intact cohesin function is dispensable for Cbfb::MYH11-driven leukemia. Instead, Cbfb::MYH11 expression is the primary driver of the transcriptional program in transformed leukemic cells. Furthermore, we observed differential effects of Rad21 and Smc3 deletion on leukemia development and secondary engraftment despite only minor differences in gene expression. These results demonstrate that cohesin mutations are not only tolerated in Cbfb::MYH11-expressing cells, but they also likely do not confer a strong selective advantage and are therefore not preferentially selected for during clonal evolution of this leukemia.
{"title":"Cohesin haploinsufficiency is tolerated in Cbfb::MYH11-driven murine acute myeloid leukemia","authors":"Shannon E. Conneely , Alexis Quezada , Kristen J. Kurtz , Nenggang Zhang , Josephine De La Fuente , Nesa Mercer , Jason H. Rogers , Rogelio Aguilar , Geraldo Medrano , Margaret A. Goodell , Paul P. Liu , Debananda Pati , Rachel E. Rau","doi":"10.1016/j.exphem.2025.105287","DOIUrl":"10.1016/j.exphem.2025.105287","url":null,"abstract":"<div><div>Cohesin gene mutations occur in many malignancies, including acute myeloid leukemia (AML). Loss-of-function mutations in the four major cohesin complex genes (<em>RAD21, SMC3, SMC1a,</em> and <em>STAG2</em>) occur across most major genetic subtypes of AML but are notably absent in AML harboring <em>CBFB::MYH11</em>, suggesting that cohesin mutations yield distinct biological outcomes dependent on the genetic AML driver. We hypothesized that <em>CBFB::MYH11</em>-expressing leukemias would be dependent on intact cohesin genes given their near-mutual exclusivity. To investigate this, we combined either germline or inducible heterozygous deletions in cohesin genes <em>Smc3</em> or <em>Rad21</em>, respectively, with an inducible murine model of <em>Cbfb::MYH11</em> AML. This approach allowed us to evaluate the effects of cohesin haploinsufficiency on leukemia development, chromatin accessibility, and transcriptional output. We demonstrated that intact cohesin function is dispensable for <em>Cbfb::MYH11</em>-driven leukemia. Instead, <em>Cbfb::MYH11</em> expression is the primary driver of the transcriptional program in transformed leukemic cells. Furthermore, we observed differential effects of <em>Rad21</em> and <em>Smc3</em> deletion on leukemia development and secondary engraftment despite only minor differences in gene expression. These results demonstrate that cohesin mutations are not only tolerated in <em>Cbfb::MYH11</em>-expressing cells, but they also likely do not confer a strong selective advantage and are therefore not preferentially selected for during clonal evolution of this leukemia.</div></div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"153 ","pages":"Article 105287"},"PeriodicalIF":2.1,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145421525","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 : 2026-01-01Epub Date: 2025-10-29DOI: 10.1016/j.exphem.2025.105285
Isabel M. Forlastro , Norah L. Smith , Emily N. Kulp , Momoko Yoshimoto , Brian D. Rudd
During the development of the immune system, there is a progressive shift from fast-acting innate-like lymphocytes to slower-acting adaptive lymphocytes. This developmental shift is evident in B cells, γδ T cells, and αβ T cells, with the more innate-like lineages (B1a, B1b, Vδ1, virtual memory CD8+, iNKT, and CD8αα) being produced before the more adaptive lineages (B2, Vγ9Vδ2, and conventional CD8+ and CD4+ αβ T cells). However, immunologists have historically viewed the development of B and γδ T cells differently than αβ T cells. Whereas it is well accepted that the functions of B and γδ T cells are linked to their derivation from distinct hematopoietic progenitors that arise throughout ontogeny, the same phenomenon has largely been ignored for αβ T cells. Instead, the prevailing view is that all αβ T cells are made from the same hematopoietic stem cells (HSCs), and any diversity in the αβ T-cell compartment comes from stochastic expression of different TCRs and random environmental cues encountered in the thymus. In this review, we discussed the evidence that αβ T-cell lineage decisions are not solely determined by thymic selection and that hematopoietic origin also intrinsically biases development toward innate-like T cells in early life.
{"title":"Developmental hematopoiesis: innate programming of αβ T cells","authors":"Isabel M. Forlastro , Norah L. Smith , Emily N. Kulp , Momoko Yoshimoto , Brian D. Rudd","doi":"10.1016/j.exphem.2025.105285","DOIUrl":"10.1016/j.exphem.2025.105285","url":null,"abstract":"<div><div>During the development of the immune system, there is a progressive shift from fast-acting innate-like lymphocytes to slower-acting adaptive lymphocytes. This developmental shift is evident in B cells, γδ T cells, and αβ T cells, with the more innate-like lineages (B1a, B1b, Vδ1, virtual memory CD8+, iNKT, and CD8αα) being produced before the more adaptive lineages (B2, Vγ9Vδ2, and conventional CD8+ and CD4+ αβ T cells). However, immunologists have historically viewed the development of B and γδ T cells differently than αβ T cells. Whereas it is well accepted that the functions of B and γδ T cells are linked to their derivation from distinct hematopoietic progenitors that arise throughout ontogeny, the same phenomenon has largely been ignored for αβ T cells. Instead, the prevailing view is that all αβ T cells are made from the same hematopoietic stem cells (HSCs), and any diversity in the αβ T-cell compartment comes from stochastic expression of different TCRs and random environmental cues encountered in the thymus. In this review, we discussed the evidence that αβ T-cell lineage decisions are not solely determined by thymic selection and that hematopoietic origin also intrinsically biases development toward innate-like T cells in early life.</div></div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"153 ","pages":"Article 105285"},"PeriodicalIF":2.1,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145421558","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 : 2026-01-01Epub Date: 2025-10-25DOI: 10.1016/j.exphem.2025.105284
Kyoko Ochiai , Kazuhiko Igarashi
Antibody maturation (involving somatic hypermutation, affinity maturation, and class switch recombination of antibody genes) occurs before plasma cell differentiation and enhances host defense against infectious agents. Various gene regulatory networks regulate antibody maturation via multiple transcription factors (TFs), which, in turn, are often regulated via different intracellular signaling pathways. BTB and CNC homolog 2 (BACH2) is an essential TF for antibody maturation as it suppresses premature plasma cell differentiation. BACH2 mainly functions as a repressor by recognizing Maf recognition elements (MAREs) and recruits repressor complexes, such as heterochromatin factors and histone deacetylation complexes, to regulatory regions. Following antigen stimulation, BACH2 expression and function are sequentially switched on and off via feedback loops during antigen-specific antibody production. This study aimed to comprehensively review the BACH2 function and regulation in B cells, including heterochromatin formation, along with the role of TFs and kinases involved in BACH2 expression and protein stability. Additionally, the review discusses the recent findings on the potential mechanisms elucidating the dynamic roles of BACH2 associated with B and/or plasma cells. Lastly, the review explores the involvement of aberrant function of BACH2 as an exacerbating factor for the onset of B-cell malignancies, along with its possible oncogenic roles and its network as a therapeutic target.
{"title":"Feedback loops in B-cell chromatin regulation as a therapeutic target for modulating antibody production and malignancies: insights from BACH2","authors":"Kyoko Ochiai , Kazuhiko Igarashi","doi":"10.1016/j.exphem.2025.105284","DOIUrl":"10.1016/j.exphem.2025.105284","url":null,"abstract":"<div><div>Antibody maturation (involving somatic hypermutation, affinity maturation, and class switch recombination of antibody genes) occurs before plasma cell differentiation and enhances host defense against infectious agents. Various gene regulatory networks regulate antibody maturation via multiple transcription factors (TFs), which, in turn, are often regulated via different intracellular signaling pathways. BTB and CNC homolog 2 (BACH2) is an essential TF for antibody maturation as it suppresses premature plasma cell differentiation. BACH2 mainly functions as a repressor by recognizing Maf recognition elements (MAREs) and recruits repressor complexes, such as heterochromatin factors and histone deacetylation complexes, to regulatory regions. Following antigen stimulation, BACH2 expression and function are sequentially switched on and off via feedback loops during antigen-specific antibody production. This study aimed to comprehensively review the BACH2 function and regulation in B cells, including heterochromatin formation, along with the role of TFs and kinases involved in BACH2 expression and protein stability. Additionally, the review discusses the recent findings on the potential mechanisms elucidating the dynamic roles of BACH2 associated with B and/or plasma cells. Lastly, the review explores the involvement of aberrant function of BACH2 as an exacerbating factor for the onset of B-cell malignancies, along with its possible oncogenic roles and its network as a therapeutic target.</div></div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"153 ","pages":"Article 105284"},"PeriodicalIF":2.1,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145616246","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 : 2026-01-01Epub Date: 2025-09-12DOI: 10.1016/j.exphem.2025.105251
Kyle D. Timmer , Daniel J. Floyd , Nathan E. Jeffries , Elizabeth C. Trull , Emma E. Yvanovich , Orion Furmanski , Kristin Gilchrist , George Klarmann , Shenglin Mei , Jelena Milosevic , Vincent B. Ho , David B. Sykes , Michael K. Mansour
Neutrophils serve as the first line of defense against invasive bacterial and fungal pathogens. The loss of circulating neutrophils leaves patients at a critical risk of life-threatening infections. In this study, we optimized conditions for expanding human precursor neutrophils ex vivo while preserving the functional capacity of mature neutrophils. We evaluated several CD34+ hematopoietic stem cells (HSCs) from various sources, including umbilical cord blood (UCB), adult bone marrow (BM), and cadaveric sources. UCB-derived CD34+ cells consistently demonstrated the highest expansion capacity, achieving an additional two cell divisions compared with BM-derived cells. Surface receptor profiling demonstrated that all sources resulted in mature neutrophil differentiation, although UCB-derived cell sources exhibited higher expression of maturation markers CD11b, CD15, and CD66b, in conditions expanded with the small molecule UM729. Functionally, neutrophils derived from all cell sources retained the ability to phagocytose and produce reactive oxygen species (ROS), with enhanced activity following antibody-dependent opsonization. To better understand the impact of opsonization, Fc receptor expression levels were assessed in addition to profiling changes in complement and adhesion receptor expression. Single-cell expression analysis confirmed that ex vivo differentiation was consistent with known patterns of myeloid differentiation, leading to distinct neutrophil subpopulations. Notably, mature neutrophils generated ex vivo were transcriptionally distinct from freshly isolated primary cells. Overall, our findings demonstrate that UCB-derived precursors offer the highest expansion potential for generating neutrophil precursors, able to mature into fully functional neutrophils. These results provide valuable insights into optimizing human neutrophil production as a promising cellular therapy for neutropenic individuals.
{"title":"Optimal ex vivo production of functional neutrophils is dependent on the source of CD34+ human hematopoietic progenitors","authors":"Kyle D. Timmer , Daniel J. Floyd , Nathan E. Jeffries , Elizabeth C. Trull , Emma E. Yvanovich , Orion Furmanski , Kristin Gilchrist , George Klarmann , Shenglin Mei , Jelena Milosevic , Vincent B. Ho , David B. Sykes , Michael K. Mansour","doi":"10.1016/j.exphem.2025.105251","DOIUrl":"10.1016/j.exphem.2025.105251","url":null,"abstract":"<div><div>Neutrophils serve as the first line of defense against invasive bacterial and fungal pathogens. The loss of circulating neutrophils leaves patients at a critical risk of life-threatening infections. In this study, we optimized conditions for expanding human precursor neutrophils ex vivo while preserving the functional capacity of mature neutrophils. We evaluated several CD34+ hematopoietic stem cells (HSCs) from various sources, including umbilical cord blood (UCB), adult bone marrow (BM), and cadaveric sources. UCB-derived CD34+ cells consistently demonstrated the highest expansion capacity, achieving an additional two cell divisions compared with BM-derived cells. Surface receptor profiling demonstrated that all sources resulted in mature neutrophil differentiation, although UCB-derived cell sources exhibited higher expression of maturation markers CD11b, CD15, and CD66b, in conditions expanded with the small molecule UM729. Functionally, neutrophils derived from all cell sources retained the ability to phagocytose and produce reactive oxygen species (ROS), with enhanced activity following antibody-dependent opsonization. To better understand the impact of opsonization, Fc receptor expression levels were assessed in addition to profiling changes in complement and adhesion receptor expression. Single-cell expression analysis confirmed that ex vivo differentiation was consistent with known patterns of myeloid differentiation, leading to distinct neutrophil subpopulations. Notably, mature neutrophils generated ex vivo were transcriptionally distinct from freshly isolated primary cells. Overall, our findings demonstrate that UCB-derived precursors offer the highest expansion potential for generating neutrophil precursors, able to mature into fully functional neutrophils. These results provide valuable insights into optimizing human neutrophil production as a promising cellular therapy for neutropenic individuals.</div></div>","PeriodicalId":12202,"journal":{"name":"Experimental hematology","volume":"153 ","pages":"Article 105251"},"PeriodicalIF":2.1,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145063867","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}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号