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更新于：2025-05-07

Hemoglobins x DNMT1

更新于：2025-05-07

基本信息

关联

项与 Hemoglobins x DNMT1 相关的药物

NSC777586

靶点

DNMT1 x Hemoglobins

作用机制

DNMT1抑制剂 [+1]

在研机构

AkiraBio, Inc. [+1]

原研机构

Augusta University [+1]

在研适应症

镰状细胞血症

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 Hemoglobins x DNMT1 相关的临床结果

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100 项与 Hemoglobins x DNMT1 相关的转化医学

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0 项与 Hemoglobins x DNMT1 相关的专利（医药）

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项与 Hemoglobins x DNMT1 相关的文献（医药）

2025-03-01·Advanced Science

Haplotype‐Resolved Genotyping and Association Analysis of 1,020 β‐Thalassemia Patients by Targeted Long‐Read Sequencing

Article

作者: Lao, Jinquan ; Xu, Xiangmin ; Huang, Zhijing ; Zhang, Xinhua ; Niu, Chao ; Qin, Lang ; Qin, Honggui ; Liu, Zhentian ; Li, Kui ; Lin, Bin ; Yu, Lian ; Huang, Li ; Huang, Yueyan ; Huang, Binbin ; Li, Yaoyun ; Tang, Deguo ; Long, Xingjiang ; Chen, Juanjuan ; Hua, Xiaoyun ; Liu, Yumeng ; Li, Jiaqi ; Qin, Jiaofeng ; Zhang, Qianqian ; Meng, Wanli ; Feng, Xiaoqin ; Lin, Wanying ; Zhu, Weijian ; Liao, Liuhua ; Zhong, Tianyu ; Fan, Chengwu ; Chen, Weijie ; Xie, Tiantian ; Liang, Yidan ; Liu, Riyang ; Ren, Zhilin ; Zhou, Xiaoman ; Qu, Xiang ; Mao, Aiping ; Liu, Qiujun ; Tan, Jufang ; Zhan, Jiahan ; Zeng, Lihong ; Yan, Lixiang ; Cai, Junqin ; Ye, Yuhua

AbstractDespite the well‐documented mutation spectra of β‐thalassemia, the genetic variants and haplotypes of globin gene clusters modulating its clinical heterogeneity remain incompletely illustrated. Here, a targeted long‐read sequencing (T‐LRS) is demonstrated to capture 20 genes/loci in 1,020 β‐thalassemia patients. This panel permits not only identification of thalassemia mutations at 100% of sensitivity and specificity, but also detection of rare structural variants (SVs) and single nucleotide variants (SNVs) in modifier genes/loci. The highly homologous regions of α‐/β‐globin gene clusters are then phased and 3 novel haplotypes in HBG1/HBG2 region are reported in this population of β‐thalassemia patients. Furthermore, one of the haplotypes is associated with ameliorated symptoms of β‐thalassemia. Similarly, 5 major haplotypes are identified in HBA1/HBA2 homologous region while one of them is found highly linked with deletional α‐thalassemia mutations. Finally, rare mutations in erythroid transcription factors in DNMT1 and KLF1 associated with increased expression of fetal hemoglobin and reduced transfusion dependencies are identified. This study presents the largest T‐LRS study for β‐thalassemia patients to date, facilitating precise clinical diagnosis and haplotype phasing of globin gene clusters.

2025-03-01·Annals of Hematology

Rapid detection of genetic modifiers of β-thalassemia based on MALDI-TOF MS

Article

作者: Zeng, Lilan ; Hua, Xiaoyun ; Huang, Li ; Long, Yong ; Dai, Tingting ; Niu, Chao ; Lin, Bin ; Ye, Yuhua ; Xu, Xiangmin ; Zhang, Qianqian ; Wang, Yuxi ; Huang, Haoyang

Fetal hemoglobin (HbF) levels are influenced by various genetic modifiers, which have clinically beneficial effects on both β-thalassemia and sickle cell disease. HbF-associated genetic variants are distributed throughout the genome, and current detection methods are often costly, time-consuming, and require multiple tests. Therefore, developing rapid and economical methods for the simultaneous detection of HbF-associated variants is essential for improving the accurate diagnosis of β-hemoglobinopathies. Matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) was employed to detect 20 well-documented genetic modifiers in BCL11A, KLF1, HBG2, DNMT1, GATAD2A, and HBS1L-MYB intergenic polymorphism (HMIP). The new assay's accuracy, repeatability, and lowest detection limit were evaluated. It was subsequently applied to 81 samples, and the clinical effects of the modifiers were further verified in a cohort of 560 β-thalassemia patients. The MALDI-TOF MS assays successfully detected all 20 genetic modifiers simultaneously in a single reaction. Genotyping results from 15 repetitions were consistent and accurate, indicating the stability of this assay. The assay's lowest detection limit for DNA was as low as 0.2 ng, sufficient for simultaneous genotyping of all loci. A double-blind evaluation of 81 samples showed 100% concordance with traditional genotyping methods. Significant differences were observed in HbF levels, survival time without transfusion, and clinical classification for the detected genetic modifiers. The MALDI-TOF MS detection assay for HbF-related variants is simple, rapid and high throughput. It enables the detection of 20 genetic modifiers in a single test, supporting accurate large-scale detection and enhancing the precise diagnosis and clinical classification of β-thalassemia.

2024-04-01·Journal of Molecular Biology

C2H2 Zinc Finger Transcription Factors Associated with Hemoglobinopathies

Review

作者: Cheng, Xiaodong ; Zhang, Xing ; Zhang, Xiaotian ; Blumenthal, Robert M ; Xia, Fangfang

In humans, specific aberrations in β-globin results in sickle cell disease and β-thalassemia, symptoms of which can be ameliorated by increased expression of fetal globin (HbF). Two recent CRISPR-Cas9 screens, centered on ∼1500 annotated sequence-specific DNA binding proteins and performed in a human erythroid cell line that expresses adult hemoglobin, uncovered four groups of candidate regulators of HbF gene expression. They are (1) members of the nucleosome remodeling and deacetylase (NuRD) complex proteins that are already known for HbF control; (2) seven C2H2 zinc finger (ZF) proteins, including some (ZBTB7A and BCL11A) already known for directly silencing the fetal γ-globin genes in adult human erythroid cells; (3) a few other transcription factors of different structural classes that might indirectly influence HbF gene expression; and (4) DNA methyltransferase 1 (DNMT1) that maintains the DNA methylation marks that attract the MBD2-associated NuRD complex to DNA as well as associated histone H3 lysine 9 methylation. Here we briefly discuss the effects of these regulators, particularly C2H2 ZFs, in inducing HbF expression for treating β-hemoglobin disorders, together with recent advances in developing safe and effective small-molecule therapeutics for the regulation of this well-conserved hemoglobin switch.

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