Pub Date : 2024-12-27DOI: 10.1182/blood.2024024130
Qi Han, Yan Gu, Huimin Xiang, Linyao Zhang, Yan Wang, Chan Yang, Jun Li, Chelsea Steiner, Rosa Lapalombella, Jennifer A Woyach, Yiping Yang, Sinisa Dovat, Chunhua Song, Zheng Ge
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy with a poor prognosis and limited options for targeted therapies. Identifying new molecular targets to develop novel therapeutic strategies is the pressing immediate issue in T-ALL. Here, we observed high expression of WD Repeat-Containing Protein 5 (WDR5) in T-ALL; with in vitro and in vivo models we demonstrated the oncogenic role of WDR5 in T-ALL by activating cell cycle signaling through its new downstream effector, ATPase family AAA domain-containing 2 (ATAD2). Moreover, IKAROS' function is often impaired by genetic alteration as well as casein kinase II (CK2) which is overexpressed in T-ALL. We found IKAROS directly regulates WDR5 transcription; CK2 inhibitor, CX-4945 strongly suppresses WDR5 expression by restoring IKAROS function. Lastly, combining CX-4945 with WDR5 inhibitor demonstrates synergistic efficacy in the patient-derived xenograft mouse models. In conclusion, our results demonstrated that WDR5/ATAD2 is a new oncogenic signaling pathway in T-ALL, and simultaneous targeting of WRD5 and CK2/IKAROS has synergistic anti-leukemic efficacy and represents a promising potential strategy for T-ALL therapy.
{"title":"Targeting WDR5/ATAD2 signaling by the CK2/Ikaros axis demonstrates therapeutic efficacy in T-ALL.","authors":"Qi Han, Yan Gu, Huimin Xiang, Linyao Zhang, Yan Wang, Chan Yang, Jun Li, Chelsea Steiner, Rosa Lapalombella, Jennifer A Woyach, Yiping Yang, Sinisa Dovat, Chunhua Song, Zheng Ge","doi":"10.1182/blood.2024024130","DOIUrl":"https://doi.org/10.1182/blood.2024024130","url":null,"abstract":"<p><p>T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy with a poor prognosis and limited options for targeted therapies. Identifying new molecular targets to develop novel therapeutic strategies is the pressing immediate issue in T-ALL. Here, we observed high expression of WD Repeat-Containing Protein 5 (WDR5) in T-ALL; with in vitro and in vivo models we demonstrated the oncogenic role of WDR5 in T-ALL by activating cell cycle signaling through its new downstream effector, ATPase family AAA domain-containing 2 (ATAD2). Moreover, IKAROS' function is often impaired by genetic alteration as well as casein kinase II (CK2) which is overexpressed in T-ALL. We found IKAROS directly regulates WDR5 transcription; CK2 inhibitor, CX-4945 strongly suppresses WDR5 expression by restoring IKAROS function. Lastly, combining CX-4945 with WDR5 inhibitor demonstrates synergistic efficacy in the patient-derived xenograft mouse models. In conclusion, our results demonstrated that WDR5/ATAD2 is a new oncogenic signaling pathway in T-ALL, and simultaneous targeting of WRD5 and CK2/IKAROS has synergistic anti-leukemic efficacy and represents a promising potential strategy for T-ALL therapy.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142944653","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 : 2024-12-27DOI: 10.1182/blood.2024026312
Nataly Cruz-Rodriguez,Michael W Deininger
Starting with imatinib, tyrosine kinase inhibitors (TKIs) have turned chronic myeloid leukemia (CML) from a lethal blood cancer into a chronic condition. As patients with access to advanced CML care have an almost normal life expectancy, there is a perception that CML is a problem of the past, and one should direct research resources elsewhere. However, a closer look at the current CML landscape reveals a more nuanced picture. Most patients still require life-long TKI therapy to avoid recurrence of active CML. Chronic TKI toxicity and the high costs of the well-tolerated agents remain challenging. Progression to blast phase still occurs, particularly in socioeconomically disadvantaged parts of the world, where high risk CML at diagnosis is common. Here we will review the prospects of further improving TKIs to achieve optimal suppression of BCR::ABL1 kinase activity, the potential of combining different classes of TKIs, and the current state of BCR::ABL1 degraders. We will cover combination therapy approaches to address TKI resistance in the setting of residual leukemia and in advanced CML. Despite the unprecedented success of TKIs in CML, more work is needed to truly finish the job, and we hope to stimulate innovative research aiming to achieve this goal.
{"title":"Novel Treatment Strategies for Chronic Myeloid Leukemia.","authors":"Nataly Cruz-Rodriguez,Michael W Deininger","doi":"10.1182/blood.2024026312","DOIUrl":"https://doi.org/10.1182/blood.2024026312","url":null,"abstract":"Starting with imatinib, tyrosine kinase inhibitors (TKIs) have turned chronic myeloid leukemia (CML) from a lethal blood cancer into a chronic condition. As patients with access to advanced CML care have an almost normal life expectancy, there is a perception that CML is a problem of the past, and one should direct research resources elsewhere. However, a closer look at the current CML landscape reveals a more nuanced picture. Most patients still require life-long TKI therapy to avoid recurrence of active CML. Chronic TKI toxicity and the high costs of the well-tolerated agents remain challenging. Progression to blast phase still occurs, particularly in socioeconomically disadvantaged parts of the world, where high risk CML at diagnosis is common. Here we will review the prospects of further improving TKIs to achieve optimal suppression of BCR::ABL1 kinase activity, the potential of combining different classes of TKIs, and the current state of BCR::ABL1 degraders. We will cover combination therapy approaches to address TKI resistance in the setting of residual leukemia and in advanced CML. Despite the unprecedented success of TKIs in CML, more work is needed to truly finish the job, and we hope to stimulate innovative research aiming to achieve this goal.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"54 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142887459","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 : 2024-12-26DOI: 10.1182/blood.2024024599
Yu Wang, Greggory Myers, Lei Yu, Kaiwen Deng, Ginette Balbin-Cuesta, Sharon A Singh, Yuanfang Guan, Rami Khoriaty, James Douglas Engel
Abstract: Nuclear receptor TR4 (NR2C2) was previously shown to bind to the -117 position of the γ-globin gene promoters in vitro, which overlaps the more recently described BCL11 transcription factor A (BCL11A) binding site. The role of TR4 in human γ-globin gene repression has not been extensively characterized in vivo, whereas any relationship between TR4 and BCL11A regulation through the γ-globin promoters is unclear at present. We show here that TR4 and BCL11A competitively bind in vitro to distinct, overlapping sequences, including positions overlapping -117 of the γ-globin promoter. We found that TR4 represses γ-globin transcription and fetal hemoglobin accumulation in vivo in a BCL11A-independent manner. Finally, examination of the chromatin occupancy of TR4 within the β-globin locus, compared with BCL11A, shows that both bind avidly to the locus control region and other sites, but only BCL11A binds to the γ-globin promoters at statistically significant frequency. These data resolve an important discrepancy in the literature and, thus, clarify possible approaches to the treatment of sickle cell disease and β-thalassaemia.
{"title":"TR4 and BCL11A repress γ-globin transcription via independent mechanisms.","authors":"Yu Wang, Greggory Myers, Lei Yu, Kaiwen Deng, Ginette Balbin-Cuesta, Sharon A Singh, Yuanfang Guan, Rami Khoriaty, James Douglas Engel","doi":"10.1182/blood.2024024599","DOIUrl":"10.1182/blood.2024024599","url":null,"abstract":"<p><strong>Abstract: </strong>Nuclear receptor TR4 (NR2C2) was previously shown to bind to the -117 position of the γ-globin gene promoters in vitro, which overlaps the more recently described BCL11 transcription factor A (BCL11A) binding site. The role of TR4 in human γ-globin gene repression has not been extensively characterized in vivo, whereas any relationship between TR4 and BCL11A regulation through the γ-globin promoters is unclear at present. We show here that TR4 and BCL11A competitively bind in vitro to distinct, overlapping sequences, including positions overlapping -117 of the γ-globin promoter. We found that TR4 represses γ-globin transcription and fetal hemoglobin accumulation in vivo in a BCL11A-independent manner. Finally, examination of the chromatin occupancy of TR4 within the β-globin locus, compared with BCL11A, shows that both bind avidly to the locus control region and other sites, but only BCL11A binds to the γ-globin promoters at statistically significant frequency. These data resolve an important discrepancy in the literature and, thus, clarify possible approaches to the treatment of sickle cell disease and β-thalassaemia.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"2762-2772"},"PeriodicalIF":21.0,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142406070","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 : 2024-12-26DOI: 10.1182/blood.2024025099
Louise A Tilley, Vanja Karamatic Crew, Tosti J Mankelow, Samah A AlSubhi, Benjamin Jones, Abigail Borowski, Vered Yahalom, Lilach Finkel, Belinda K Singleton, Piers J Walser, Ashley M Toye, Timothy J Satchwell, Nicole M Thornton
Abstract: The genetic background of the high prevalence red blood cell antigen AnWj has remained unresolved since its identification in 1972, despite reported associations with both CD44 and Smyd1 histone methyltransferase. Development of anti-AnWj, which may be clinically significant, is usually due to transient suppression of antigen expression, but a small number of individuals with persistent, autosomally recessive inherited AnWj-negative phenotype have been reported. Whole-exome sequencing of individuals with the rare inherited AnWj-negative phenotype revealed no shared mutations in CD44H or SMYD1; instead, we discovered homozygosity for the same large exonic deletion in MAL, which was confirmed in additional unrelated AnWj-negative individuals. MAL encodes an integral multipass membrane proteolipid, myelin and lymphocyte protein (Mal), which has been reported to have essential roles in cell transport and membrane stability. AnWj-positive individuals were shown to express full-length Mal on their red cell membranes, which was not present on the membranes of AnWj-negative individuals, regardless of whether from an inherited or suppression background. Furthermore, binding of anti-AnWj was able to inhibit binding of anti-Mal to AnWj-positive red cells, demonstrating the antibodies bind to the same molecule. Overexpression of Mal in an erythroid cell line resulted in the expression of AnWj antigen, regardless of the presence or absence of CD44, demonstrating that Mal is both necessary and sufficient for AnWj expression. Our data resolve the genetic background of the inherited AnWj-negative phenotype, forming the basis of a new blood group system, further reducing the number of remaining unsolved blood group antigens.
{"title":"Deletions in the MAL gene result in loss of Mal protein, defining the rare inherited AnWj-negative blood group phenotype.","authors":"Louise A Tilley, Vanja Karamatic Crew, Tosti J Mankelow, Samah A AlSubhi, Benjamin Jones, Abigail Borowski, Vered Yahalom, Lilach Finkel, Belinda K Singleton, Piers J Walser, Ashley M Toye, Timothy J Satchwell, Nicole M Thornton","doi":"10.1182/blood.2024025099","DOIUrl":"10.1182/blood.2024025099","url":null,"abstract":"<p><strong>Abstract: </strong>The genetic background of the high prevalence red blood cell antigen AnWj has remained unresolved since its identification in 1972, despite reported associations with both CD44 and Smyd1 histone methyltransferase. Development of anti-AnWj, which may be clinically significant, is usually due to transient suppression of antigen expression, but a small number of individuals with persistent, autosomally recessive inherited AnWj-negative phenotype have been reported. Whole-exome sequencing of individuals with the rare inherited AnWj-negative phenotype revealed no shared mutations in CD44H or SMYD1; instead, we discovered homozygosity for the same large exonic deletion in MAL, which was confirmed in additional unrelated AnWj-negative individuals. MAL encodes an integral multipass membrane proteolipid, myelin and lymphocyte protein (Mal), which has been reported to have essential roles in cell transport and membrane stability. AnWj-positive individuals were shown to express full-length Mal on their red cell membranes, which was not present on the membranes of AnWj-negative individuals, regardless of whether from an inherited or suppression background. Furthermore, binding of anti-AnWj was able to inhibit binding of anti-Mal to AnWj-positive red cells, demonstrating the antibodies bind to the same molecule. Overexpression of Mal in an erythroid cell line resulted in the expression of AnWj antigen, regardless of the presence or absence of CD44, demonstrating that Mal is both necessary and sufficient for AnWj expression. Our data resolve the genetic background of the inherited AnWj-negative phenotype, forming the basis of a new blood group system, further reducing the number of remaining unsolved blood group antigens.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"2735-2747"},"PeriodicalIF":21.0,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141999337","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 : 2024-12-26DOI: 10.1182/blood.2024026481
Andrew Charles Perkins
{"title":"Revisiting γ-globin gene repression by TR4.","authors":"Andrew Charles Perkins","doi":"10.1182/blood.2024026481","DOIUrl":"https://doi.org/10.1182/blood.2024026481","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"31 1","pages":"2691-2692"},"PeriodicalIF":20.3,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142887316","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 : 2024-12-26DOI: 10.1182/blood.2024026925
Curtis A Lachowiez, Vishvaas I Ravikumar, Jad Othman, Jenny O'Nions, Daniel T Peters, Christine McMahon, Ronan Swords, Rachel Cook, Jennifer N Saultz, Jeffrey W Tyner, Richard Dillon, Joshua F Zeidner, Daniel A Pollyea
Abstract: The European LeukemiaNet 2024 risk-stratification guidelines for patients with acute myeloid leukemia receiving hypomethylating agents combined with venetoclax were recently published. This analysis demonstrates reclassification and incorporation of new gene mutations in the present model can further improve and individualize prognostication.
{"title":"Refined ELN 2024 risk stratification improves survival prognostication following venetoclax-based therapy in AML.","authors":"Curtis A Lachowiez, Vishvaas I Ravikumar, Jad Othman, Jenny O'Nions, Daniel T Peters, Christine McMahon, Ronan Swords, Rachel Cook, Jennifer N Saultz, Jeffrey W Tyner, Richard Dillon, Joshua F Zeidner, Daniel A Pollyea","doi":"10.1182/blood.2024026925","DOIUrl":"10.1182/blood.2024026925","url":null,"abstract":"<p><strong>Abstract: </strong>The European LeukemiaNet 2024 risk-stratification guidelines for patients with acute myeloid leukemia receiving hypomethylating agents combined with venetoclax were recently published. This analysis demonstrates reclassification and incorporation of new gene mutations in the present model can further improve and individualize prognostication.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"2788-2792"},"PeriodicalIF":21.0,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142575038","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 : 2024-12-26DOI: 10.1182/blood.2024024519
Akshay Sharma
Abstract: In 2023, 2 different gene therapies were approved for individuals with severe sickle cell disease (SCD). The small number of patients treated on the pivotal clinical trials that led to these approvals have experienced dramatic short-term reductions in the occurrence of painful vaso-occlusive crises, but the long-term safety and efficacy of these genetic therapies are yet to be ascertained. Several challenges and treatment-related concerns have emerged in regard to administering these therapies in clinical practice. This article discusses the selection and preparation of individuals with SCD who wish to receive autologous gene therapy, as well as the salient features of the care needed to support them through a long and arduous treatment process. I specifically focus on postinfusion care, as it relates to immune monitoring and infection prevention. Compared with allogeneic hematopoietic cell transplantation, delivering autologous gene therapy to an individual with SCD has distinct nuances that require awareness and special interventions. Using clinical vignettes derived from real-life patients, I provide perspectives on the complex decision-making process for gene therapy for SCD based on currently available data and make recommendations for evaluating and supporting these patients.
{"title":"How I treat sickle cell disease with gene therapy.","authors":"Akshay Sharma","doi":"10.1182/blood.2024024519","DOIUrl":"10.1182/blood.2024024519","url":null,"abstract":"<p><strong>Abstract: </strong>In 2023, 2 different gene therapies were approved for individuals with severe sickle cell disease (SCD). The small number of patients treated on the pivotal clinical trials that led to these approvals have experienced dramatic short-term reductions in the occurrence of painful vaso-occlusive crises, but the long-term safety and efficacy of these genetic therapies are yet to be ascertained. Several challenges and treatment-related concerns have emerged in regard to administering these therapies in clinical practice. This article discusses the selection and preparation of individuals with SCD who wish to receive autologous gene therapy, as well as the salient features of the care needed to support them through a long and arduous treatment process. I specifically focus on postinfusion care, as it relates to immune monitoring and infection prevention. Compared with allogeneic hematopoietic cell transplantation, delivering autologous gene therapy to an individual with SCD has distinct nuances that require awareness and special interventions. Using clinical vignettes derived from real-life patients, I provide perspectives on the complex decision-making process for gene therapy for SCD based on currently available data and make recommendations for evaluating and supporting these patients.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"2693-2705"},"PeriodicalIF":21.0,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142364348","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 : 2024-12-26DOI: 10.1182/blood.2024026752
Marta M Szmyra-Połomka,Alexander J A Deutsch
{"title":"Early adaptations to survive venetoclax therapy.","authors":"Marta M Szmyra-Połomka,Alexander J A Deutsch","doi":"10.1182/blood.2024026752","DOIUrl":"https://doi.org/10.1182/blood.2024026752","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"150 1","pages":"2689-2691"},"PeriodicalIF":20.3,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142887460","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 : 2024-12-26DOI: 10.1182/blood.2024026378
Jill R Storry,Slim Azouzi
{"title":"An uncommon MALady: is the AnWj puzzle complete?","authors":"Jill R Storry,Slim Azouzi","doi":"10.1182/blood.2024026378","DOIUrl":"https://doi.org/10.1182/blood.2024026378","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"14 1","pages":"2688-2689"},"PeriodicalIF":20.3,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142887462","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}