Pub Date : 2026-03-11DOI: 10.1038/s41375-026-02905-6
Sanam Loghavi,Aziz Farhat,Trevor J Jamison,Georgina El Hajjar,Alex Bataller,Sa A Wang,Wei Wang,Guilin Tang,Andres E Quesada,Alexandre Bazinet,Branko Cuglievan,Courtney D DiNardo,Guillermo Montalban-Bravo,Koichi Takahashi,Nicholas J Short,Hussein A Abbas,Tapan Kadia,Farhad Ravandi,Naval Daver,Elias Jabbour,Gautam Borthakur,Michael Andreeff,L Jeffrey Medeiros,Hagop M Kantarjian,Ghayas C Issa
Menin inhibition leads to an antileukemic effect through hematopoietic differentiation. Treatment with the menin inhibitor revumenib results in clinical remissions in relapsed or refractory (R/R) acute myeloid leukemia (AML) with either rearrangement of lysine methyltransferase 2A (KMT2A) or mutation in nucleophosmin 1 (NPM1), leading to regulatory approval of this drug. However, determinants of response to revumenib have not been fully elucidated. We examined the immunophenotype of leukemia cells by flow cytometry, in sequential bone marrow specimens from 48 patients with R/R AML treated with revumenib. We observed dynamic changes in the immunophenotype after treatment in 16 of 31 (52%) patients, characterized by a switch from a myeloid/stem-like to a monocytic or myelomonocytic immunophenotype, or vice versa, or by substantial changes in the intensity of antigen expression or in patterns of leukemia-associated immunophenotypes. Morphologic remission with undetectable measurable residual disease (MRD) by flow cytometry following revumenib was associated with improved overall survival, with a median of 23.6 months compared with 20.8 months in patients with morphologic response and detectable MRD, and 3.2 months in non-responders. In summary, treatment monitoring of AML by flow cytometry, following menin inhibition, requires recognition of phenotypic changes associated with differentiation.
{"title":"Immunophenotypic changes following menin inhibition in acute myeloid leukemia.","authors":"Sanam Loghavi,Aziz Farhat,Trevor J Jamison,Georgina El Hajjar,Alex Bataller,Sa A Wang,Wei Wang,Guilin Tang,Andres E Quesada,Alexandre Bazinet,Branko Cuglievan,Courtney D DiNardo,Guillermo Montalban-Bravo,Koichi Takahashi,Nicholas J Short,Hussein A Abbas,Tapan Kadia,Farhad Ravandi,Naval Daver,Elias Jabbour,Gautam Borthakur,Michael Andreeff,L Jeffrey Medeiros,Hagop M Kantarjian,Ghayas C Issa","doi":"10.1038/s41375-026-02905-6","DOIUrl":"https://doi.org/10.1038/s41375-026-02905-6","url":null,"abstract":"Menin inhibition leads to an antileukemic effect through hematopoietic differentiation. Treatment with the menin inhibitor revumenib results in clinical remissions in relapsed or refractory (R/R) acute myeloid leukemia (AML) with either rearrangement of lysine methyltransferase 2A (KMT2A) or mutation in nucleophosmin 1 (NPM1), leading to regulatory approval of this drug. However, determinants of response to revumenib have not been fully elucidated. We examined the immunophenotype of leukemia cells by flow cytometry, in sequential bone marrow specimens from 48 patients with R/R AML treated with revumenib. We observed dynamic changes in the immunophenotype after treatment in 16 of 31 (52%) patients, characterized by a switch from a myeloid/stem-like to a monocytic or myelomonocytic immunophenotype, or vice versa, or by substantial changes in the intensity of antigen expression or in patterns of leukemia-associated immunophenotypes. Morphologic remission with undetectable measurable residual disease (MRD) by flow cytometry following revumenib was associated with improved overall survival, with a median of 23.6 months compared with 20.8 months in patients with morphologic response and detectable MRD, and 3.2 months in non-responders. In summary, treatment monitoring of AML by flow cytometry, following menin inhibition, requires recognition of phenotypic changes associated with differentiation.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"7 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2026-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147393807","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Whether mitigation of myeloproliferation improves prognosis of CMML independently of bone marrow response is unknown. Flow-defined classical monocytes (cMo) and immature granulocytes (iGRAN) have not yet been studied as biomarkers of response. We inspected the prognostic value of WBC, circulating monocytes, cMo and iGRANs in the 120 DACOTA (NCT02214407) patients randomized to decitabine (n = 63) or hydroxyurea (n = 57) evaluated after 3 cycles with BM aspiration and complete blood count. Across arms, 59% and 56% patients had monocytes > 1 × 109/L or WBC > 10 × 109/L at the 3- and 6-cycle evaluation respectively. After 6 cycles, persistence of monocytes > 1 × 109/L or WBC > 10 × 109/L increased the hazard of death (HR = 5.38, p = 0.0003) irrespective of treatment, baseline CPSS and persistence of BM blast excess. After 3 cycles, both higher absolute cMo and iGRAN counts independently predicted poorer OS, without significant interaction with treatment arm. Median OS from landmark was 35.1 months in the 28% patients with cMo ≤ 0.94 ×109/L AND iGRAN ≤ 0.40 ×109/L versus 15.3 months in others (p = 0.013). Biomarkers integrating blood counts and flow cytometry may predict CMML prognosis irrespective of treatment.
{"title":"Does stringent cytoreduction improve survival in advanced proliferative chronic myelomonocytic leukemia?","authors":"Dorothée Selimoglu-Buet,Sylvie Chevret,Valeria Santini,Sylvain Thépot,Margot Morabito,Lionel Adès,Lucie Laplane,Aristoteles Giagounidis,Nathalie Droin,Michael Lübbert,Rosa Sapena,Stanislas Nimubona,Jose Miguel Torregrosa-Diaz,Ulrich Germing,Anna Maria Pelizzari,Sophie Park,Nadja Jaekel,Georgia Metzgeroth,Francesco Onida,Franciane Paul,Andrea Patriarca,Aspasia Stamatoullas,Katharina Götze,Fatiha Chermat,Uwe Platzbecker,Pierre Fenaux,Eric Solary,Raphael Itzykson","doi":"10.1038/s41375-026-02901-w","DOIUrl":"https://doi.org/10.1038/s41375-026-02901-w","url":null,"abstract":"Whether mitigation of myeloproliferation improves prognosis of CMML independently of bone marrow response is unknown. Flow-defined classical monocytes (cMo) and immature granulocytes (iGRAN) have not yet been studied as biomarkers of response. We inspected the prognostic value of WBC, circulating monocytes, cMo and iGRANs in the 120 DACOTA (NCT02214407) patients randomized to decitabine (n = 63) or hydroxyurea (n = 57) evaluated after 3 cycles with BM aspiration and complete blood count. Across arms, 59% and 56% patients had monocytes > 1 × 109/L or WBC > 10 × 109/L at the 3- and 6-cycle evaluation respectively. After 6 cycles, persistence of monocytes > 1 × 109/L or WBC > 10 × 109/L increased the hazard of death (HR = 5.38, p = 0.0003) irrespective of treatment, baseline CPSS and persistence of BM blast excess. After 3 cycles, both higher absolute cMo and iGRAN counts independently predicted poorer OS, without significant interaction with treatment arm. Median OS from landmark was 35.1 months in the 28% patients with cMo ≤ 0.94 ×109/L AND iGRAN ≤ 0.40 ×109/L versus 15.3 months in others (p = 0.013). Biomarkers integrating blood counts and flow cytometry may predict CMML prognosis irrespective of treatment.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"50 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2026-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147381240","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-09DOI: 10.1038/s41375-026-02907-4
Portia Smallbone,Kai Cao,Rima M Saliba,Yudith Carmarzzi,Gheath Al-Atrash,Michele Alvarez,Gabriela Rondon,Warren B Fingrut,Yosra M Aljawai,Amanda L Olson,Amin M Alousi,George L Chen,Mark R Tanner,Jun Zou,Jeremy L Ramdial,Richard E Champlin,Elizabeth J Shpall,Betül Oran
Disease progression, graft-versus-host disease (GVHD), and non-relapse mortality (NRM) are the main causes of failure after allogeneic hematopoietic cell transplantation (SCT) for myeloid neoplasms. T-cell epitope-based models classify HLA-DPB1 mismatches by permissiveness and have been associated with differential risks of GVHD, relapse, and NRM. However, most studies were conducted before the routine use of post-transplant cyclophosphamide (PTCy) as GVHD prophylaxis for unrelated donor (UD) SCT. We retrospectively analyzed 541 adults undergoing 8/8 UD SCT with PTCy prophylaxis, categorized as DP-matched (DP-M, n = 176), permissive mismatch (DP-P, n = 219), non-permissive graft-versus-host (DP-NP-GVH, n = 82), or host-versus-graft (DP-NP-HVG, n = 64). Outcomes were compared across groups with stratification by disease risk and remission/MRD status. Two-year relapse incidence was lower with DP-P versus DP-M (18% vs 28%; HR 0.6, 95% CI 0.4-0.9, p = 0.03), most pronounced in high-risk AML/MDS, where relapse rates approached those of lower-risk disease. This effect persisted after adjustment for remission and MRD status. GVHD incidence was unaffected by DPB1 status. OS and PFS did not differ significantly; age and comorbidity were dominant predictors of NRM. In UD SCT with PTCy, DPB1-permissive mismatching reduces relapse in high-risk AML/MDS without increasing GVHD or NRM, supporting DP-P mismatching as an actionable donor-selection criterion.
疾病进展、移植物抗宿主病（GVHD）和非复发死亡率（NRM）是髓系肿瘤同种异体造血细胞移植（SCT）失败的主要原因。基于t细胞表位的模型根据允许度对HLA-DPB1错配进行分类，并与GVHD、复发和NRM的不同风险相关。然而，大多数研究是在非亲属供者（UD） SCT常规使用移植后环磷酰胺（PTCy）作为GVHD预防之前进行的。我们回顾性分析了541名接受8/8 UD SCT并进行PTCy预防的成年人，分为dp -匹配（DP-M, n = 176）、容许性错配（DP-P, n = 219）、非容许性移植物抗宿主（DP-NP-GVH, n = 82）或宿主抗移植物（DP-NP-HVG, n = 64）。通过疾病风险和缓解/MRD状态分层对各组结果进行比较。DP-P与DP-M的两年复发率较低（18% vs 28%; HR 0.6, 95% CI 0.4-0.9, p = 0.03），在高危AML/MDS中最为明显，复发率接近低危疾病。这种效果在调整缓解和MRD状态后仍然存在。GVHD的发病率不受DPB1状态的影响。OS与PFS无显著差异；年龄和合并症是NRM的主要预测因素。在合并PTCy的UD SCT中，dpp1允许型错配减少了高风险AML/MDS的复发，而不会增加GVHD或NRM，支持DP-P错配作为可行的供体选择标准。
{"title":"Reduced relapse in high risk acute myeloid leukemia and myelodysplastic neoplasms with permissive HLA-DPB1 mismatches and post-transplant cyclophosphamide.","authors":"Portia Smallbone,Kai Cao,Rima M Saliba,Yudith Carmarzzi,Gheath Al-Atrash,Michele Alvarez,Gabriela Rondon,Warren B Fingrut,Yosra M Aljawai,Amanda L Olson,Amin M Alousi,George L Chen,Mark R Tanner,Jun Zou,Jeremy L Ramdial,Richard E Champlin,Elizabeth J Shpall,Betül Oran","doi":"10.1038/s41375-026-02907-4","DOIUrl":"https://doi.org/10.1038/s41375-026-02907-4","url":null,"abstract":"Disease progression, graft-versus-host disease (GVHD), and non-relapse mortality (NRM) are the main causes of failure after allogeneic hematopoietic cell transplantation (SCT) for myeloid neoplasms. T-cell epitope-based models classify HLA-DPB1 mismatches by permissiveness and have been associated with differential risks of GVHD, relapse, and NRM. However, most studies were conducted before the routine use of post-transplant cyclophosphamide (PTCy) as GVHD prophylaxis for unrelated donor (UD) SCT. We retrospectively analyzed 541 adults undergoing 8/8 UD SCT with PTCy prophylaxis, categorized as DP-matched (DP-M, n = 176), permissive mismatch (DP-P, n = 219), non-permissive graft-versus-host (DP-NP-GVH, n = 82), or host-versus-graft (DP-NP-HVG, n = 64). Outcomes were compared across groups with stratification by disease risk and remission/MRD status. Two-year relapse incidence was lower with DP-P versus DP-M (18% vs 28%; HR 0.6, 95% CI 0.4-0.9, p = 0.03), most pronounced in high-risk AML/MDS, where relapse rates approached those of lower-risk disease. This effect persisted after adjustment for remission and MRD status. GVHD incidence was unaffected by DPB1 status. OS and PFS did not differ significantly; age and comorbidity were dominant predictors of NRM. In UD SCT with PTCy, DPB1-permissive mismatching reduces relapse in high-risk AML/MDS without increasing GVHD or NRM, supporting DP-P mismatching as an actionable donor-selection criterion.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"15 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2026-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147381241","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-06DOI: 10.1038/s41375-026-02898-2
Linyao Zhang,Qi Han,Huimin Xiang,Rosa Lapalombella,Ann-Kathrin Eisfeld,Walter G Hanel,Jonathan E Brammer,Alice S Mims,Jennifer A Woyach,Chunhua Song,Zheng Ge
Many patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) are still less sensitive to tyrosine kinase inhibitors (TKIs). Ph+ ALL shows a high incidence of IKZF1 deletions. Casein kinase II (CK2)-mediated hyperphosphorylation of IKZF1, encoding protein IKAROS, contributes to its dysfunction, and CK2 inhibitor, CX-4945, restores IKAROS function in high-risk ALL. Here, we found that Ph+ ALL cells with IKZF1 deletion are inherently resistant to TKIs. The combination of TKIs (imatinib or ponatinib) with CX-4945 significantly extended the survival and reduced the tumor burden in the IKZF1 deletion (Ik6+) Ph+ ALL patient-derived xenograft (PDX) mouse model; particularly, the patient died of relapse shortly after treatment with the third-generation TKI and the CD19/CD3 bispecific antibody blinatumomab. GLUT1 is highly expressed in the Ph+ ALL and associated with synergy of TKIs with CX-4945; Seahorse assay showed enhanced glycolysis in the patient sample with Ik6+ Ph+ ALL; GLUT1 knockdown suppresses glycolysis and induces apoptosis in the cells. The combination of TKIs with CX-4945 demonstrates the synergistic efficacy through restoring IKAROS transcriptional repression of GLUT1 and further suppressing glycolysis in Ph+ ALL. Our results identify new mechanisms underlying TKI sensitivity and novel approaches to overcome TKI resistance through transcriptional repression of the key genes in glycolysis in Ph+ ALL.
{"title":"Enhancing tyrosine kinase inhibitor sensitivity by restoring IKAROS activity on GLUT1 expression and glycolysis in Philadelphia chromosome-positive acute lymphoblastic leukemia.","authors":"Linyao Zhang,Qi Han,Huimin Xiang,Rosa Lapalombella,Ann-Kathrin Eisfeld,Walter G Hanel,Jonathan E Brammer,Alice S Mims,Jennifer A Woyach,Chunhua Song,Zheng Ge","doi":"10.1038/s41375-026-02898-2","DOIUrl":"https://doi.org/10.1038/s41375-026-02898-2","url":null,"abstract":"Many patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) are still less sensitive to tyrosine kinase inhibitors (TKIs). Ph+ ALL shows a high incidence of IKZF1 deletions. Casein kinase II (CK2)-mediated hyperphosphorylation of IKZF1, encoding protein IKAROS, contributes to its dysfunction, and CK2 inhibitor, CX-4945, restores IKAROS function in high-risk ALL. Here, we found that Ph+ ALL cells with IKZF1 deletion are inherently resistant to TKIs. The combination of TKIs (imatinib or ponatinib) with CX-4945 significantly extended the survival and reduced the tumor burden in the IKZF1 deletion (Ik6+) Ph+ ALL patient-derived xenograft (PDX) mouse model; particularly, the patient died of relapse shortly after treatment with the third-generation TKI and the CD19/CD3 bispecific antibody blinatumomab. GLUT1 is highly expressed in the Ph+ ALL and associated with synergy of TKIs with CX-4945; Seahorse assay showed enhanced glycolysis in the patient sample with Ik6+ Ph+ ALL; GLUT1 knockdown suppresses glycolysis and induces apoptosis in the cells. The combination of TKIs with CX-4945 demonstrates the synergistic efficacy through restoring IKAROS transcriptional repression of GLUT1 and further suppressing glycolysis in Ph+ ALL. Our results identify new mechanisms underlying TKI sensitivity and novel approaches to overcome TKI resistance through transcriptional repression of the key genes in glycolysis in Ph+ ALL.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"2 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2026-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147368370","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-05DOI: 10.1038/s41375-026-02909-2
Tania Setiawan, Jabir Aliyu Muhammad, Nadya Marcelina Julianto, Lawrence Mario Wirawan, Nayoung Jun, Ita Novita Sari, Vivian G Oehler, Dong-Wook Kim, Hyog Young Kwon
{"title":"Correction: Regulation of metabolic adaptation and leukemia progression by MUSASHI2-DEPTOR-KIF11 axis.","authors":"Tania Setiawan, Jabir Aliyu Muhammad, Nadya Marcelina Julianto, Lawrence Mario Wirawan, Nayoung Jun, Ita Novita Sari, Vivian G Oehler, Dong-Wook Kim, Hyog Young Kwon","doi":"10.1038/s41375-026-02909-2","DOIUrl":"https://doi.org/10.1038/s41375-026-02909-2","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":" ","pages":""},"PeriodicalIF":13.4,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147365654","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-26DOI: 10.1038/s41375-026-02892-8
Jonas S Jutzi, Edie Crosse, Chulwoo J Kim, Bob van Gasteren, Charles Laurore, Benjamin Rolles, Frederike Kramer, Anastasia Tishena, Azucena V Rocha, Mohammed Wazir, Lachelle D Weeks, Joan How, Maximilian Stahl, Marlise R Luskin, R Coleman Lindsley, Olga Pozdnyakova, Sumit Rai, Timothy A Graubert, Robert K Bradley, Ann Mullally, Anna E Marneth
Somatic mutations in RNA splicing regulators, including the serine/arginine-rich protein SRSF2, are frequently observed in myeloid malignancies. Using mouse models and primary human samples, we investigated the impact of SRSF2 mutations on erythropoiesis. We found reduced erythropoiesis in Srsf2P95H versus wild-type mice upon stress-induced erythropoiesis and identified that SRSF2 mutations correlate with reduced hemoglobin in JAK2-mutant patients with myeloproliferative neoplasms (MPN). Consistent with this, Jak2V617F-Srsf2P95H versus Jak2V617F mice displayed reduced red blood cell counts and erythroid precursor frequencies. RNA-sequencing on erythroid precursors showed reduced expression of heme metabolism and mitotic spindle-related genes, and increased expression of mTORC1 signaling in Srsf2P95H versus wild-type cells. RNA splicing analyses on the same cells and on human patient samples identified aberrant FYN splicing in SRSF2mut cells, with increased aberrant FYNB over normal FYNT transcripts. FYNB, but not FYNT, expression resulted in reduced erythroid differentiation and increased phosphorylation of mTORC1 downstream target S6. Additionally, increased S6 phosphorylation was confirmed in primary Srsf2P95H erythroid cells. mTORC1 pathway inhibition using rapamycin normalized FYNB- and Srsf2P95H-induced impaired erythropoiesis and significantly increased erythroid colony formation of SRSF2-mutant myelodysplastic neoplasm (MDS) bone marrow cells. Our data reveal targetable molecular mechanisms of impaired erythropoiesis in SRSF2-mutant cells.
{"title":"Mutant SRSF2-associated impaired erythropoiesis is defined by increased mTORC1 signaling due to FYN missplicing.","authors":"Jonas S Jutzi, Edie Crosse, Chulwoo J Kim, Bob van Gasteren, Charles Laurore, Benjamin Rolles, Frederike Kramer, Anastasia Tishena, Azucena V Rocha, Mohammed Wazir, Lachelle D Weeks, Joan How, Maximilian Stahl, Marlise R Luskin, R Coleman Lindsley, Olga Pozdnyakova, Sumit Rai, Timothy A Graubert, Robert K Bradley, Ann Mullally, Anna E Marneth","doi":"10.1038/s41375-026-02892-8","DOIUrl":"https://doi.org/10.1038/s41375-026-02892-8","url":null,"abstract":"<p><p>Somatic mutations in RNA splicing regulators, including the serine/arginine-rich protein SRSF2, are frequently observed in myeloid malignancies. Using mouse models and primary human samples, we investigated the impact of SRSF2 mutations on erythropoiesis. We found reduced erythropoiesis in Srsf2<sup>P95H</sup> versus wild-type mice upon stress-induced erythropoiesis and identified that SRSF2 mutations correlate with reduced hemoglobin in JAK2-mutant patients with myeloproliferative neoplasms (MPN). Consistent with this, Jak2<sup>V617F</sup>-Srsf2<sup>P95H</sup> versus Jak2<sup>V617F</sup> mice displayed reduced red blood cell counts and erythroid precursor frequencies. RNA-sequencing on erythroid precursors showed reduced expression of heme metabolism and mitotic spindle-related genes, and increased expression of mTORC1 signaling in Srsf2<sup>P95H</sup> versus wild-type cells. RNA splicing analyses on the same cells and on human patient samples identified aberrant FYN splicing in SRSF2<sup>mut</sup> cells, with increased aberrant FYNB over normal FYNT transcripts. FYNB, but not FYNT, expression resulted in reduced erythroid differentiation and increased phosphorylation of mTORC1 downstream target S6. Additionally, increased S6 phosphorylation was confirmed in primary Srsf2<sup>P95H</sup> erythroid cells. mTORC1 pathway inhibition using rapamycin normalized FYNB- and Srsf2<sup>P95H</sup>-induced impaired erythropoiesis and significantly increased erythroid colony formation of SRSF2-mutant myelodysplastic neoplasm (MDS) bone marrow cells. Our data reveal targetable molecular mechanisms of impaired erythropoiesis in SRSF2-mutant cells.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":" ","pages":""},"PeriodicalIF":13.4,"publicationDate":"2026-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147306833","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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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