Pub Date : 2026-03-12DOI: 10.1182/blood.2025032408
Robert J Soiffer
{"title":"Graft manipulation and GVHD: what goes around comes around.","authors":"Robert J Soiffer","doi":"10.1182/blood.2025032408","DOIUrl":"https://doi.org/10.1182/blood.2025032408","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"147 11","pages":"1137-1138"},"PeriodicalIF":23.1,"publicationDate":"2026-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147430516","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 : 2026-03-11DOI: 10.1182/blood.2025030962
Huiying Zhi,Douglas Sheridan,Peter J Newman,Debra K Newman
Fetal/neonatal alloimmune thrombocytopenia (FNAIT) is a bleeding disorder in which maternal antibodies target fetal and neonatal platelet alloantigens, most commonly human platelet alloantigen-1a (HPA-1a), resulting in fetal and neonatal thrombocytopenia severe enough to cause life-threatening organ bleeds, such as intracranial hemorrhage. Hemolytic disease of the fetus and newborn (HDFN) is an analogous disease caused by maternal exposure to fetal red blood cell (RBC) alloantigens, most commonly because of postpartum fetal maternal hemorrhage (FMH), that can be prevented by prophylactic administration of fetal RBC-specific antibodies. Unlike HDFN, the events that trigger FNAIT are unknown and can occur during first pregnancies, making FNAIT difficult to predict and prevent. Herein, we investigated the ability of in utero FMH to induce maternal alloimmunization to HPA-1a and cause FNAIT in a preclinical model. Transfusion of HPA-1a-positive platelets into wild-type (WT) mice in numbers representing moderate and severe FMH in humans induced production of equivalent levels of HPA-1a-specific antibodies in non-pregnant mice and mice pregnant with WT or HPA-1a-positive fetuses, causing FNAIT in the latter. Administration to pregnant females of the HPA-1a-specific monoclonal antibody RLYB212/mAb 26.4 prevented FMH-induced maternal alloimmunization to HPA-1a and FNAIT in genetically susceptible pups. In mice pregnant with HPA-1a-positive fetuses but not exposed to FMH, administration of RLYB212/mAb 26.4 did not cause FNAIT. Together, these findings identify in utero FMH as a potential trigger for maternal alloimmunization to fetal HPA-1a and provide proof of concept that prophylactic administration of HPA-1a-specific antibodies may safely and effectively prevent FMH-induced FNAIT in at-risk pregnancies.
{"title":"Transfusing HPA-mismatched platelets to mimic fetomaternal hemorrhage elicits fetal/neonatal alloimmune thrombocytopenia.","authors":"Huiying Zhi,Douglas Sheridan,Peter J Newman,Debra K Newman","doi":"10.1182/blood.2025030962","DOIUrl":"https://doi.org/10.1182/blood.2025030962","url":null,"abstract":"Fetal/neonatal alloimmune thrombocytopenia (FNAIT) is a bleeding disorder in which maternal antibodies target fetal and neonatal platelet alloantigens, most commonly human platelet alloantigen-1a (HPA-1a), resulting in fetal and neonatal thrombocytopenia severe enough to cause life-threatening organ bleeds, such as intracranial hemorrhage. Hemolytic disease of the fetus and newborn (HDFN) is an analogous disease caused by maternal exposure to fetal red blood cell (RBC) alloantigens, most commonly because of postpartum fetal maternal hemorrhage (FMH), that can be prevented by prophylactic administration of fetal RBC-specific antibodies. Unlike HDFN, the events that trigger FNAIT are unknown and can occur during first pregnancies, making FNAIT difficult to predict and prevent. Herein, we investigated the ability of in utero FMH to induce maternal alloimmunization to HPA-1a and cause FNAIT in a preclinical model. Transfusion of HPA-1a-positive platelets into wild-type (WT) mice in numbers representing moderate and severe FMH in humans induced production of equivalent levels of HPA-1a-specific antibodies in non-pregnant mice and mice pregnant with WT or HPA-1a-positive fetuses, causing FNAIT in the latter. Administration to pregnant females of the HPA-1a-specific monoclonal antibody RLYB212/mAb 26.4 prevented FMH-induced maternal alloimmunization to HPA-1a and FNAIT in genetically susceptible pups. In mice pregnant with HPA-1a-positive fetuses but not exposed to FMH, administration of RLYB212/mAb 26.4 did not cause FNAIT. Together, these findings identify in utero FMH as a potential trigger for maternal alloimmunization to fetal HPA-1a and provide proof of concept that prophylactic administration of HPA-1a-specific antibodies may safely and effectively prevent FMH-induced FNAIT in at-risk pregnancies.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"18 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2026-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147393806","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 : 2026-03-11DOI: 10.1182/blood.2025030972
Li Gao,Xiaowen Zhai,Ningling Wang,Ning Liao,Peifang Xiao,Fang Xu,Minghua Yang,Xueju Xu,Qi An,Jixia Luo,Liangchun Yang,Xiaojun Yuan,Yunyan He,Yong Zhuang,Hongsheng Wang,Linhai Yang,Weina Zhang,Yufeng Liu Liu,Jie Li,Hailong He,Yi Wang,Cheng Cheng,Jun Lu,Hua Jiang,Xiuli Ju,Qianfei Wang,Raul C Ribeiro,Shaoyan Hu
Intensive chemotherapy is standard for AML but carries high risks of life-threatening complications, particularly in vulnerable patients. We aimed to compare the efficacy and safety of a low-dose chemotherapy (LDC) regimen for induction of AML. A randomized, multicenter, noninferiority trial was conducted in patients aged <18 years with AML. Patients received low-dose cytarabine, mitoxantrone or idarubicin, and G-CSF (LDC) or standard-dose induction chemotherapy (SDC) (cytarabine, daunomycin, and etoposide). All patients received post-remission consolidation with standard chemotherapy and/ or hematopoietic stem cell transplantation. The primary endpoint was to compare response rates between treatments. The secondary endpoints were to compare the outcomes, toxicity, and safety of the LDC and SDC regimens. The two treatment arms showed no significant differences in outcomes. Complete remission (CR/CRi) rates after induction were 95.1% and 95.3% in the LDC and SDC arms, respectively. Measurable residual disease < 0.1% after induction II was observed in 87.4% and 87.1% of patients in the LDC and SDC arms, respectively. Median time to neutrophil and platelet recovery was significantly shorter among patients receiving the LDC regimen. Patients in the LDC arm had a 4-year overall survival (OS) of 81.3% vs. 83.6% (P = .611) and a 4-year event-free survival (EFS) of 61.5% vs. 63.1% (P = .832). In conclusion, the LDC regimen was well tolerated and was associated with CR, EFS, and OS rates that were not inferior to those of patients treated with the SDC regimen. The trial was registered at Chinese Clinical Trial Registry (ChiCTR1800015883).
强化化疗是急性髓性白血病的标准治疗方法，但有很高的危及生命的并发症风险，特别是在脆弱的患者中。我们的目的是比较低剂量化疗（LDC）方案诱导AML的有效性和安全性。一项随机、多中心、非劣效性试验在年龄<18岁的AML患者中进行。患者接受低剂量阿糖胞苷、米托蒽醌或伊达柔比星、G-CSF （LDC）或标准剂量诱导化疗（SDC）（阿糖胞苷、道诺霉素和依托泊苷）。所有患者在缓解后均接受标准化疗和/或造血干细胞移植。主要终点是比较不同治疗的有效率。次要终点是比较LDC和SDC方案的结局、毒性和安全性。两个治疗组在结果上没有显著差异。诱导后完全缓解（CR/CRi）率在最不发达组和最不发达组分别为95.1%和95.3%。在LDC组和SDC组中，分别有87.4%和87.1%的患者在诱导II后可测量的残留疾病< 0.1%。在接受LDC方案的患者中，中性粒细胞和血小板恢复的中位时间显着缩短。最不发达组患者的4年总生存率（OS）为81.3% vs. 83.6% (P = 0.611)， 4年无事件生存率（EFS）为61.5% vs. 63.1% （P = 0.832）。总之，LDC方案耐受性良好，与CR、EFS和OS率相关，不低于SDC方案治疗的患者。该试验已在中国临床试验注册中心注册（ChiCTR1800015883）。
{"title":"A low- versus standard-dose regimen as induction for pediatric AML: a multicenter, randomized noninferiority trial.","authors":"Li Gao,Xiaowen Zhai,Ningling Wang,Ning Liao,Peifang Xiao,Fang Xu,Minghua Yang,Xueju Xu,Qi An,Jixia Luo,Liangchun Yang,Xiaojun Yuan,Yunyan He,Yong Zhuang,Hongsheng Wang,Linhai Yang,Weina Zhang,Yufeng Liu Liu,Jie Li,Hailong He,Yi Wang,Cheng Cheng,Jun Lu,Hua Jiang,Xiuli Ju,Qianfei Wang,Raul C Ribeiro,Shaoyan Hu","doi":"10.1182/blood.2025030972","DOIUrl":"https://doi.org/10.1182/blood.2025030972","url":null,"abstract":"Intensive chemotherapy is standard for AML but carries high risks of life-threatening complications, particularly in vulnerable patients. We aimed to compare the efficacy and safety of a low-dose chemotherapy (LDC) regimen for induction of AML. A randomized, multicenter, noninferiority trial was conducted in patients aged <18 years with AML. Patients received low-dose cytarabine, mitoxantrone or idarubicin, and G-CSF (LDC) or standard-dose induction chemotherapy (SDC) (cytarabine, daunomycin, and etoposide). All patients received post-remission consolidation with standard chemotherapy and/ or hematopoietic stem cell transplantation. The primary endpoint was to compare response rates between treatments. The secondary endpoints were to compare the outcomes, toxicity, and safety of the LDC and SDC regimens. The two treatment arms showed no significant differences in outcomes. Complete remission (CR/CRi) rates after induction were 95.1% and 95.3% in the LDC and SDC arms, respectively. Measurable residual disease < 0.1% after induction II was observed in 87.4% and 87.1% of patients in the LDC and SDC arms, respectively. Median time to neutrophil and platelet recovery was significantly shorter among patients receiving the LDC regimen. Patients in the LDC arm had a 4-year overall survival (OS) of 81.3% vs. 83.6% (P = .611) and a 4-year event-free survival (EFS) of 61.5% vs. 63.1% (P = .832). In conclusion, the LDC regimen was well tolerated and was associated with CR, EFS, and OS rates that were not inferior to those of patients treated with the SDC regimen. The trial was registered at Chinese Clinical Trial Registry (ChiCTR1800015883).","PeriodicalId":9102,"journal":{"name":"Blood","volume":"15 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2026-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147393810","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 : 2026-03-10DOI: 10.1182/blood.2025032216
Bernd B Zeisig,Mohammad M Karimi,Chi Wai Eric So
Transposable elements (TEs) are emerging regulators of hematopoiesis and leukemia, creating vulnerabilities exploitable for therapy. Recent evidence shows that TE reactivation induces innate immune signalling, DNA damage responses and dependence on Poly(ADP-ribose) polymerase (PARP)-mediated protection, enabling synthetic lethality with PARP inhibition even in homologous-recombination-proficient leukemias with epigenetic gene mutations. In this article, we highlight the biology underpinning this novel TE-PARP axis, its therapeutic implications and strategies to expand beyond HR-deficient cancers through rational combinations with immunotherapy and refined patient stratification.
{"title":"The Transposable Element-PARP Axis Underpins Synthetic Lethality and Immunogenic Vulnerability in Blood Cancer.","authors":"Bernd B Zeisig,Mohammad M Karimi,Chi Wai Eric So","doi":"10.1182/blood.2025032216","DOIUrl":"https://doi.org/10.1182/blood.2025032216","url":null,"abstract":"Transposable elements (TEs) are emerging regulators of hematopoiesis and leukemia, creating vulnerabilities exploitable for therapy. Recent evidence shows that TE reactivation induces innate immune signalling, DNA damage responses and dependence on Poly(ADP-ribose) polymerase (PARP)-mediated protection, enabling synthetic lethality with PARP inhibition even in homologous-recombination-proficient leukemias with epigenetic gene mutations. In this article, we highlight the biology underpinning this novel TE-PARP axis, its therapeutic implications and strategies to expand beyond HR-deficient cancers through rational combinations with immunotherapy and refined patient stratification.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"198 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2026-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147393808","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: 10.1182/blood.2025030059
Lukas M Braun,Jarushka Naidoo,Robert Zeiser
Immunotherapies, such as allogeneic hematopoietic cell transplantation and infusion of chimeric antigen receptor T (CAR-T) cells have significantly extended our therapeutic armamentarium against several hematological malignancies. Blocking negative regulators of immunity with immune checkpoint inhibitors has significantly improved the survival of patients with mainly solid tumors. Despite their beneficial effects, these therapies are also associated with severe, immune-mediated side effects. Here, we discuss biological similarities and differences of acute graft-versus-host disease (GVHD), cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), immune effector cell-associated hemophagocytic lymphohistiocytosis like syndrome (IEC-HS), immune effector cell-associated hematotoxicity (ICAHT), local immune effector cell-associated toxicity syndrome (LICATS), and immune-related adverse events after immune checkpoint inhibition (irAEs). Recent data have led to a better understanding of the role of myeloid cells and T-cells, including tissue-resident T-cells, in the pathophysiology of GVHD, CAR-T-cell associated immunotoxicities and irAEs. Further, we summarize approved, currently evaluated and potential future therapies for immune-mediated toxicities of cancer immunotherapies. This review will help to understand how therapeutic strategies target communalities of different side effects to overcome immune-mediated side effects of cancer immunotherapies.
{"title":"Immune-mediated side effects of cancer immunotherapies.","authors":"Lukas M Braun,Jarushka Naidoo,Robert Zeiser","doi":"10.1182/blood.2025030059","DOIUrl":"https://doi.org/10.1182/blood.2025030059","url":null,"abstract":"Immunotherapies, such as allogeneic hematopoietic cell transplantation and infusion of chimeric antigen receptor T (CAR-T) cells have significantly extended our therapeutic armamentarium against several hematological malignancies. Blocking negative regulators of immunity with immune checkpoint inhibitors has significantly improved the survival of patients with mainly solid tumors. Despite their beneficial effects, these therapies are also associated with severe, immune-mediated side effects. Here, we discuss biological similarities and differences of acute graft-versus-host disease (GVHD), cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), immune effector cell-associated hemophagocytic lymphohistiocytosis like syndrome (IEC-HS), immune effector cell-associated hematotoxicity (ICAHT), local immune effector cell-associated toxicity syndrome (LICATS), and immune-related adverse events after immune checkpoint inhibition (irAEs). Recent data have led to a better understanding of the role of myeloid cells and T-cells, including tissue-resident T-cells, in the pathophysiology of GVHD, CAR-T-cell associated immunotoxicities and irAEs. Further, we summarize approved, currently evaluated and potential future therapies for immune-mediated toxicities of cancer immunotherapies. This review will help to understand how therapeutic strategies target communalities of different side effects to overcome immune-mediated side effects of cancer immunotherapies.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"7 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2026-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147381239","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: 10.1182/blood.2025031883
William Grant Dunn,Michael Charles Sachs,Matteo Maggi,Muxin Gu,Pedro M Quiros,Kiran Batta,Christen Lykkegaard Andersen,Margarete A Fabre,Timothy J Chevassut,Irina Mohorianu,Daniel Howard Wiseman,George S Vassiliou
The terms clonal monocytosis of undetermined significance (CMUS) and clonal cytopenia and monocytosis of undetermined significance (CCMUS) were introduced by the International Consensus Classification of Myeloid Neoplasms (ICC) to describe cases of clonal hematopoiesis (CH) and a concurrent monocytosis, that did not meet the diagnostic criteria of chronic myelomonocytic leukemia (CMML). To date, their practical relevance as clinicopathological entities at a population level has not been assessed. Here, we assess the prevalence, significance and natural history of CMUS and CCMUS amongst 431,531 UK Biobank participants through analysis of clinical, genomic and health outcome data. We find that CMUS with an absolute monocytosis and CCMUS are high-risk entities strongly associated with incident myeloid neoplasia (MN), cardiovascular and renal disease. Noting the overall higher monocyte counts in men and the low rate of progression of DNMT3A-CMUS, we show that amending the definition of CMUS/CCMUS to incorporate sex-specific monocyte thresholds and the exclusion of isolated DNMT3A mutations from the definition significantly strengthens the association with incident MN. Finally, given their association with poor outcomes, we develop MoSAIC, a machine learning classifier to infer the presence of SRSF2 mutations (associated with high MN risk) amongst individuals with monocytosis, based on complete blood count indices alone. We corroborate our findings in an independent cohort of 625,328 Danish primary care patients. Our findings underscore the clinical relevance of CMUS and CCMUS as distinct high-risk states within the spectrum of clonal hematopoiesis, and establish an evidence base to refine their diagnostic definition.
{"title":"The prevalence and clinical significance of clonal monocytosis.","authors":"William Grant Dunn,Michael Charles Sachs,Matteo Maggi,Muxin Gu,Pedro M Quiros,Kiran Batta,Christen Lykkegaard Andersen,Margarete A Fabre,Timothy J Chevassut,Irina Mohorianu,Daniel Howard Wiseman,George S Vassiliou","doi":"10.1182/blood.2025031883","DOIUrl":"https://doi.org/10.1182/blood.2025031883","url":null,"abstract":"The terms clonal monocytosis of undetermined significance (CMUS) and clonal cytopenia and monocytosis of undetermined significance (CCMUS) were introduced by the International Consensus Classification of Myeloid Neoplasms (ICC) to describe cases of clonal hematopoiesis (CH) and a concurrent monocytosis, that did not meet the diagnostic criteria of chronic myelomonocytic leukemia (CMML). To date, their practical relevance as clinicopathological entities at a population level has not been assessed. Here, we assess the prevalence, significance and natural history of CMUS and CCMUS amongst 431,531 UK Biobank participants through analysis of clinical, genomic and health outcome data. We find that CMUS with an absolute monocytosis and CCMUS are high-risk entities strongly associated with incident myeloid neoplasia (MN), cardiovascular and renal disease. Noting the overall higher monocyte counts in men and the low rate of progression of DNMT3A-CMUS, we show that amending the definition of CMUS/CCMUS to incorporate sex-specific monocyte thresholds and the exclusion of isolated DNMT3A mutations from the definition significantly strengthens the association with incident MN. Finally, given their association with poor outcomes, we develop MoSAIC, a machine learning classifier to infer the presence of SRSF2 mutations (associated with high MN risk) amongst individuals with monocytosis, based on complete blood count indices alone. We corroborate our findings in an independent cohort of 625,328 Danish primary care patients. Our findings underscore the clinical relevance of CMUS and CCMUS as distinct high-risk states within the spectrum of clonal hematopoiesis, and establish an evidence base to refine their diagnostic definition.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"81 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2026-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147381238","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: 10.1182/blood.2025031402
Danika Di Giacomo,Petri Pölönen,Valentina Bardelli,Shunsuke Kimura,Valentina Pierini,Luca Pagliaro,Silvia Arniani,Yunchao Chang,Qingsong Gao,Lindsey E Montefiori,Yiming Wu,Chun Shik Park,William C Wright,Federica Vento,Huimei Wei,Caterina Matteucci,Shaohua Lei,Wojciech Rosikiewicz,Carlotta Nardelli,Anair Graciela Lema Fernandez,Anna Østergaard,Emily A Backhaus,Pradyumna Baviskar,Marco Cerrano,Matteo Leoncin,Atsushi Manabe,Shinsuke Hirabayashi,Junko Takita,Daisuke Hasegawa,Satoshi Miyamoto,Antonio Macchiarulo,Jason Xu,David Trent Teachey,Giovanni Roti,Ilaria Iacobucci,Roberta La Starza,Cristina Mecucci,Charles G Mullighan
Despite great progress in understanding the genomic basis of immature T-cell acute lymphoblastic leukemia/lymphoblastic lymphoma (T-ALL) and acute leukemias of ambiguous lineage (ALAL), there are still cases that lack defining genetic markers, complicating risk stratification and limiting targeted therapeutic options. Recent studies have shown that enhancer hijacking drives oncogene activation in approximately half of T-ALL cases, with the BCL11B enhancer frequently involved. Here, we describe a subtype of leukemia with a distinct gene expression signature, and immunophenotype characterized by positivity for immature (CD38), myeloid (CD13), T-lymphoid (cytoplasmic (c)CD3, CD7), and B-lymphoid markers (CD19, CD79a, CD10). This subtype is defined by the t(14;16)(q32;q24) translocation, which places the FOXF1 gene and its antisense long noncoding RNA gene FENDRR under the regulatory control of the BCL11B enhancer, leading to their ectopic transcriptional activation. Common concomitant genetic lesions are loss-of-function alterations of GATA3, CDKN2A/CDKN2B deletion and activating JAK/STAT and NOTCH1 pathway mutations. Patients were predominantly children and adolescents/young adults (AYA) and experienced poor treatment outcome. High-throughput drug screening of 176 compounds demonstrated efficacy of combined BCL2-family proteins and JAK/STAT signaling inhibitors. Additionally, the clinical use of tyrosine kinase inhibitors in some of these cases showed therapeutic efficacy. Collectively, these findings identify BCL11B-enhancer mediated deregulation of FOXF1/FENDRR as a hallmark of a subtype of high-risk lineage ambiguous leukemia that is potentially amenable to targeted therapeutic intervention.
{"title":"Deregulation of FOXF1/FENDRR from t(14;16)(q32;q24) defines a subtype of high-risk lineage ambiguous leukemia.","authors":"Danika Di Giacomo,Petri Pölönen,Valentina Bardelli,Shunsuke Kimura,Valentina Pierini,Luca Pagliaro,Silvia Arniani,Yunchao Chang,Qingsong Gao,Lindsey E Montefiori,Yiming Wu,Chun Shik Park,William C Wright,Federica Vento,Huimei Wei,Caterina Matteucci,Shaohua Lei,Wojciech Rosikiewicz,Carlotta Nardelli,Anair Graciela Lema Fernandez,Anna Østergaard,Emily A Backhaus,Pradyumna Baviskar,Marco Cerrano,Matteo Leoncin,Atsushi Manabe,Shinsuke Hirabayashi,Junko Takita,Daisuke Hasegawa,Satoshi Miyamoto,Antonio Macchiarulo,Jason Xu,David Trent Teachey,Giovanni Roti,Ilaria Iacobucci,Roberta La Starza,Cristina Mecucci,Charles G Mullighan","doi":"10.1182/blood.2025031402","DOIUrl":"https://doi.org/10.1182/blood.2025031402","url":null,"abstract":"Despite great progress in understanding the genomic basis of immature T-cell acute lymphoblastic leukemia/lymphoblastic lymphoma (T-ALL) and acute leukemias of ambiguous lineage (ALAL), there are still cases that lack defining genetic markers, complicating risk stratification and limiting targeted therapeutic options. Recent studies have shown that enhancer hijacking drives oncogene activation in approximately half of T-ALL cases, with the BCL11B enhancer frequently involved. Here, we describe a subtype of leukemia with a distinct gene expression signature, and immunophenotype characterized by positivity for immature (CD38), myeloid (CD13), T-lymphoid (cytoplasmic (c)CD3, CD7), and B-lymphoid markers (CD19, CD79a, CD10). This subtype is defined by the t(14;16)(q32;q24) translocation, which places the FOXF1 gene and its antisense long noncoding RNA gene FENDRR under the regulatory control of the BCL11B enhancer, leading to their ectopic transcriptional activation. Common concomitant genetic lesions are loss-of-function alterations of GATA3, CDKN2A/CDKN2B deletion and activating JAK/STAT and NOTCH1 pathway mutations. Patients were predominantly children and adolescents/young adults (AYA) and experienced poor treatment outcome. High-throughput drug screening of 176 compounds demonstrated efficacy of combined BCL2-family proteins and JAK/STAT signaling inhibitors. Additionally, the clinical use of tyrosine kinase inhibitors in some of these cases showed therapeutic efficacy. Collectively, these findings identify BCL11B-enhancer mediated deregulation of FOXF1/FENDRR as a hallmark of a subtype of high-risk lineage ambiguous leukemia that is potentially amenable to targeted therapeutic intervention.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"6 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2026-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147368259","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: 10.1182/blood.2025028762
Bethany Verkamp, Michael B Jordan, Carl E Allen
Abstract: Pediatric hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome, characterized by heightened T-cell activation and overwhelming interferon gamma production. Rather than a binary "primary" vs "secondary" framework, it is best conceptualized as a threshold phenomenon that occurs when combined genetic and environmental factors exceed a critical tipping point, leading to a recognizable clinical pattern of abnormal immunopathology. In addition to classic genetic cytotoxic defects, an increasing number of genetic lesions continue to be recognized as related to HLH. Environmental triggers frequently include malignancy, infection, and rheumatologic disorders, and identifying underlying factors driving HLH is a crucial component of evaluation. The revised HLH-2004 criteria are an important tool in promptly recognizing HLH, but clinical criteria may be fulfilled by other inflammatory disorders. Genetic and functional immune testing are complementary tools for diagnosis and establishing recurrence risk. Dexamethasone and etoposide remain cornerstones of initial therapy but are best used in an individualized, response-based manner with close monitoring of inflammatory markers. Newer, more targeted agents continue to emerge and are often critical additions for achieving disease control. Most patients with inherited cytotoxic defects and other select causes require hematopoietic cell transplant for cure, which should occur as soon as feasible once adequate, not perfect, HLH control is established to minimize risk of reactivation, infection, and toxicity. This review aims to highlight key advancements in defining, diagnosing, and treating HLH based on a growing understanding of HLH pathophysiology. We also provide perspectives on practical clinical approaches that may be useful for diagnosing and treating pediatric HLH.
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Pub Date : 2026-03-05DOI: 10.1182/blood.2025031787
Fateeha Furqan,Paolo Strati
{"title":"Could a TCR be faster than a CAR?","authors":"Fateeha Furqan,Paolo Strati","doi":"10.1182/blood.2025031787","DOIUrl":"https://doi.org/10.1182/blood.2025031787","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"3 1","pages":"1008-1010"},"PeriodicalIF":20.3,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147350493","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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