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Targeting WDR5/ATAD2 signaling by the CK2/Ikaros axis demonstrates therapeutic efficacy in T-ALL.
IF 21 1区 医学 Q1 HEMATOLOGY Pub Date : 2024-12-27 DOI: 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.

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引用次数: 0
Novel Treatment Strategies for Chronic Myeloid Leukemia.
IF 20.3 1区 医学 Q1 HEMATOLOGY Pub Date : 2024-12-27 DOI: 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.
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引用次数: 0
TR4 and BCL11A repress γ-globin transcription via independent mechanisms. TR4和BCL11A通过独立机制抑制γ-球蛋白转录
IF 21 1区 医学 Q1 HEMATOLOGY Pub Date : 2024-12-26 DOI: 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.

核受体 TR4 曾在体外与 -globin 基因启动子的 -117 位点结合,该位点与最近描述的 BCL11A 结合位点重叠。TR4 在人类 -globin 基因抑制中的作用尚未在体内得到广泛表征,而 TR4 与 BCL11A 通过 -globin 启动子进行调控之间的任何关系目前还不清楚。我们在此表明,TR4 和 BCL11A 在体外竞争性地结合到不同的重叠序列上,包括与 -globin 启动子 -117 重叠的位置。我们发现,TR4以一种与BCL11A无关的方式抑制了-球蛋白的转录和HbF在体内的积累。最后,与 BCL11A 相比,对 -globin 基因座内 TR4 的染色质占有率进行的研究表明,两者都与基因座控制区和其他位点紧密结合,但只有 BCL11A 与 -globin 启动子结合的频率具有统计学意义。这些数据解决了文献中的一个重要差异,从而明确了治疗镰状细胞病和 -地中海贫血症的可能方法。
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引用次数: 0
Deletions in the MAL gene result in loss of Mal protein, defining the rare inherited AnWj-negative blood group phenotype. MAL 基因缺失会导致 Mal 蛋白缺失,从而形成罕见的 AnWj 阴性血型遗传表型。
IF 21 1区 医学 Q1 HEMATOLOGY Pub Date : 2024-12-26 DOI: 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.

自 1972 年鉴定出高发红细胞抗原 AnWj 以来,尽管有报道称它与 CD44 和 Smyd1 组蛋白甲基转移酶都有关联,但其遗传背景仍未得到解决。抗 AnWj 的出现可能具有临床意义,但通常是由于抗原表达的短暂抑制所致,但也有报道称少数人具有持续的、常染色体隐性遗传的 AnWj 阴性表型。对具有罕见遗传性 AnWj 阴性表型的个体进行全外显子组测序后发现,CD44H 或 SMYD1 没有共同的突变,相反,我们发现了 MAL 中相同的大外显子缺失的同源性,这在其他无关的 AnWj 阴性个体中也得到了证实。MAL 编码一种完整的多通道膜蛋白脂质--髓鞘和淋巴细胞蛋白(Mal),据报道它在细胞运输和膜稳定性方面发挥着重要作用。研究表明,AnWj 阳性个体的红细胞膜上表达全长的 Mal,而 AnWj 阴性个体(无论是遗传背景还是抑制背景)的红细胞膜上则不表达 Mal。此外,抗AnWj的结合能够抑制抗Mal与AnWj阳性红细胞的结合,这表明抗体与同一分子结合。在红细胞系中过度表达Mal会导致AnWj抗原的表达,而与CD44的存在与否无关,这表明Mal对AnWj的表达既是必要的也是充分的。我们的数据揭示了遗传性 AnWj 阴性表型的遗传背景,为建立新的血型系统奠定了基础,进一步减少了尚未解决的血型抗原数量。
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引用次数: 0
Auer rod-like inclusions in B-cell lymphoma mimicking therapy-related acute myeloid leukemia.
IF 20.3 1区 医学 Q1 HEMATOLOGY Pub Date : 2024-12-26 DOI: 10.1182/blood.2024025759
Elena Frye Naharro,Michael A Linden
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引用次数: 0
Revisiting γ-globin gene repression by TR4.
IF 20.3 1区 医学 Q1 HEMATOLOGY Pub Date : 2024-12-26 DOI: 10.1182/blood.2024026481
Andrew Charles Perkins
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引用次数: 0
Refined ELN 2024 risk stratification improves survival prognostication following venetoclax-based therapy in AML. 完善的ELN 2024风险分层改善了基于venetoclax疗法的急性髓细胞白血病患者的生存预后。
IF 21 1区 医学 Q1 HEMATOLOGY Pub Date : 2024-12-26 DOI: 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.

最近发布了针对接受低甲基化药物联合 Venetoclax 治疗的急性髓性白血病患者的 ELN 2024 风险分级指南。这项分析表明,在目前的模型中重新分类并纳入新的基因突变,可以进一步改善预后并使之个体化。
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引用次数: 0
How I treat sickle cell disease with gene therapy. 我是如何用基因疗法治疗镰状细胞病的
IF 21 1区 医学 Q1 HEMATOLOGY Pub Date : 2024-12-26 DOI: 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.

2023 年,两种不同的基因疗法获准用于重症镰状细胞病(SCD)患者。在这些获批的关键临床试验中,接受治疗的少数患者在短期内大幅减少了痛苦的血管闭塞性危象的发生,但这些基因疗法的长期安全性和有效性仍有待确定。在临床实践中使用这些疗法时,出现了一些挑战和与治疗相关的问题。在本文中,我将讨论希望接受自体基因疗法的 SCD 患者的选择和准备。我还回顾了在漫长而艰辛的治疗过程中为他们提供支持所需的护理的突出特点。我特别关注输注后的护理,因为这与免疫监测和感染预防有关。与同种异体造血细胞移植相比,为 SCD 患者提供自体基因治疗具有独特的细微差别,需要提高认识并采取特殊干预措施。我利用来自真实患者的临床案例,根据目前可用的数据,从复杂的决策过程角度为 SCD 的基因治疗提供视角,并为评估和支持这些患者提出建议。
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引用次数: 0
Early adaptations to survive venetoclax therapy.
IF 20.3 1区 医学 Q1 HEMATOLOGY Pub Date : 2024-12-26 DOI: 10.1182/blood.2024026752
Marta M Szmyra-Połomka,Alexander J A Deutsch
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引用次数: 0
An uncommon MALady: is the AnWj puzzle complete?
IF 20.3 1区 医学 Q1 HEMATOLOGY Pub Date : 2024-12-26 DOI: 10.1182/blood.2024026378
Jill R Storry,Slim Azouzi
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引用次数: 0
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Blood
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