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Gene Expression Profiling to Detect New Treatment Targets in Leukemia and Lymphoma: A Future Perspective
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
Torsten Haferlach, Wolfgang Kern, Alexander Kohlmann
Another approach was described by Qian et al. (21) in therapy-related AML and myeloid cell lines focussing on CD34-positive selected cells. They were the first ones to define a specific pattern of gene expression for t-AML in comparison with other AML subtypes. The most discriminating genes were found to be involved in arrested differentiation of early progenitor cells. A higher expression of cell cycle control genes such as CCNA2, CCNE2, and CDC2 and genes for cell cycle checkpoints such as BUB1 or growth (Myc) were found. Furthermore, downregulation of transcription factors involved in early hematopoiesis (TAL1, GATA1, EKLF) and overexpression of FLT3 was detected. The authors concluded that these genes may be further investigated for new targets and drugs in this very unfavourable subtype of AML.
Targeting fetal hemoglobin expression to treat β hemoglobinopathies
Published in Expert Opinion on Therapeutic Targets, 2022
Upstream of the HBG promoters are binding sites for the HbF repressor ZBTB7A (LRF) and activator KLF1. The ZBTB7A binding site ~200 bp upstream of HBG was disrupted using a C > T base editor and a new KLF1 binding site created at this locus using a A > G base editor in sickle cell disease and β-thalassemia HPSCs. Both edits reactivated the HbF genes to ~40% and corrected the sickle cell disease phenotype; introduction of a new KLF1 site best corrected the β-thalassemia phenotype [100]. Using a Cas nickase preventing double-strand breaks and DNA repair is theoretically advantageous. Only transitions are currently possible so not all sites, including the HbS mutation, are amenable to correction. While preliminary, these experiments raise the possibility that HbF gene activation can be as good as, or superior to, reversing HbF gene suppression.
Congenital Nonspherocytic Hemolytic Anemia Caused by Krüppel-Like Factor 1 Gene Variants: Another Case Report
Published in Hemoglobin, 2019
Hua Jiang, Fan Jiang, Jian Li, Fang Tang, Dong-Zhi Li
Krüppel-like factor 1 (KLF1) encoded by the KLF1 gene is a hematopoietic-specific transcription factor that induces high level expression of adult β-globin and other erythroid genes. The hematological phenotypes of individuals carrying KLF1 gene variants range from the clinically unremarkable In(Lu) blood group, to a mild increase in the levels of hemoglobin (Hb) F (α2γ2) and Hb A2 (α2δ2), to severe dyserythropoietic anemia and, in the most extreme cases, severe anemia in utero leading to hydrops fetalis [1]. An epidemiological study has found that KLF1 gene variants are relatively more common in thalassemia-endemic regions [2]. Therefore, it can be expected that compound heterozygosity or homozygosity for KLF1 gene variants will occasionally be encountered if affected patients have clinically notable presentations. In this study, we report such a case who suffered from congenital nonspherocytic hemolytic anemia (CNSHA) due to inherited compound heterozygous KLF1 gene variants.
A Krüppel-Like Factor 1 Gene Mutation Ameliorates the Severity of β-Thalassemia: A Case Report
Published in Hemoglobin, 2019
Xing-Mei Xie, Ying-Na Liu, Jian Li, Fan Jiang, Dong-Zhi Li
One of the important modifier genes is KLF1. The KLF1 gene acts as an important erythroid-specific transcription factor that regulates the development of erythrocytes [5]. By binding to the promoter of the BCL11A gene and activating its expression, KLF1 suppresses HBG1 and HBG2 gene expressions leading to γ-globin chain synthesis down-regulation [6]. The γ-globin chains along with α-globin chains make up Hb F. By these two mechanisms, KLF1 decreases Hb F levels in adults. It can be expected that KLF1 haploinsufficiency correlates with increased Hb F production caused by decreased BCL11A expression [7]. As clinical manifestations of β-thal can be modified by Hb F levels, KLF1 gene mutations would have a role in modulating the phenotypic severity of β-thal. Our twin II-2 with a KLF1 mutation had a transfusion-free survival for 4 years, while twin II-1 with no KLF1 gene mutation developed severe anemia from 4 months after birth. A recent study also reported the evidence of ameliorating the severity of β-thal by KLF1 gene mutations [8]. The mutant allele frequency of KLF1 was 1.25% in Southern Chinese subjects, and is relatively more common in a thalassemia endemic region [8]. Therefore, the exact investigation of KLF1 gene modifiers is necessary in areas where globin gene disorders are most prevalent, especially in high-risk couples for β-thal. This will be helpful in genetic counseling and optimizing the guidelines for PND programs and surveillance and treatment of β-thal.