Genetic Profiling of Acute and Chronic Leukemia via Next-Generation Sequencing: Current Insights and Future Perspectives

Hematology Reports, Journal Year: 2025, Volume and Issue: 17(2), P. 18 - 18

Published: March 28, 2025

Leukemia is a heterogeneous group of hematologic malignancies characterized by distinct genetic and molecular abnormalities. Advancements in genomic technologies have significantly transformed the diagnosis, prognosis, treatment strategies for leukemia. Among these, next-generation sequencing (NGS) has emerged as powerful tool, enabling high-resolution profiling that surpasses conventional diagnostic approaches. By providing comprehensive insights into mutations, clonal evolution, resistance mechanisms, NGS revolutionized precision medicine leukemia management. Despite its transformative potential, clinical integration presents challenges, including data interpretation complexities, standardization issues, cost considerations. However, continuous advancements platforms bioinformatics pipelines are enhancing reliability accessibility routine practice. The expanding role paving way improved risk stratification, targeted therapies, real-time disease monitoring, ultimately leading to better patient outcomes. This review highlights impact on research applications, discussing advantages over traditional techniques, key approaches, emerging challenges. As oncology continues evolve, expected play an increasingly central diagnosis management leukemia, driving innovations personalized therapeutic interventions.

Language: Английский

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Germline ERG haploinsufficiency defines a new syndrome with cytopenia and hematological malignancy predisposition

Blood, Journal Year: 2024, Volume and Issue: 144(17), P. 1765 - 1780

Published: July 11, 2024

Abstract The genomics era has facilitated the discovery of new genes that predispose individuals to bone marrow failure (BMF) and hematological malignancy (HM). We report ETS-related gene (ERG), a novel, autosomal dominant BMF/HM predisposition gene. ERG is highly constrained transcription factor critical for definitive hematopoiesis, stem cell function, platelet maintenance. colocalizes with other factors, including RUNX family 1 (RUNX1) GATA binding protein 2 (GATA2), on promoters or enhancers orchestrate hematopoiesis. identified rare heterozygous missense variant in 3 thrombocytopenia from 14 additional variants unrelated BMF/HM, de novo cases truncating variants. Phenotypes associated pathogenic germ line included cytopenias (thrombocytopenia, neutropenia, pancytopenia) HMs (acute myeloid leukemia, myelodysplastic syndrome, acute lymphoblastic leukemia) onset before 40 years. Twenty (19 truncating), population variants, were functionally characterized. Thirteen potentially erythroblast transformation specific (ETS) domain displayed loss-of-function (LOF) characteristics, thereby disrupting transcriptional transactivation, DNA binding, and/or nuclear localization. Selected overexpressed mouse fetal liver cells failed drive differentiation cytokine-independent growth culture promote erythroleukemia when transplanted into mice, concordant these being LOF Four somatic genetic rescue by copy neutral loss heterozygosity. Identification predisposing clinical implications patient diagnoses, counseling, surveillance, treatment strategies, selection donors therapy.

Language: Английский

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FLI1 is associated with regulation of DNA methylation and megakaryocytic differentiation in FPDMM caused by a RUNX1 transactivation domain mutation

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: June 18, 2024

Familial platelet disorder with associated myeloid malignancies (FPDMM) is an autosomal dominant disease caused by heterozygous germline mutations in RUNX1. It characterized thrombocytopenia, dysfunction, and a predisposition to hematological malignancies. Although FPDMM precursor for diseases involving abnormal DNA methylation, the methylation status remains unknown, largely due lack of animal models challenges obtaining patient-derived samples. Here, using genome editing techniques, we established two lines human induced pluripotent stem cells (iPSCs) different FPDMM-mimicking RUNX1 mutations. These iPSCs showed defective differentiation hematopoietic progenitor (HPCs) megakaryocytes (Mks), consistent FPDMM. The HPCs patterns distinct from those wild-type HPCs, hypermethylated regions showing enrichment ETS transcription factor (TF) motifs. We found that expression FLI1, family member, was significantly downregulated transactivation domain (TAD) mutation. demonstrated FLI1 promoted binding-site-directed demethylation, overexpression restored their megakaryocytic efficiency hypermethylation status. findings suggest plays crucial role regulating correcting TAD

Language: Английский

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DNA methylation analysis using RUNX1-mutated cells reveals association of FLI1 to familial platelet disorder with associated myeloid malignancies caused by a mutation in the transactivation domain of RUNX1

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 20, 2024

Abstract Background Familial platelet disorder with associated myeloid malignancies (FPDMM) is an autosomal dominant disease caused by heterozygous germline mutations in RUNX1 . It characterized thrombocytopenia dysfunction and a high risk of hematological malignancy development. Although FPDMM precursor condition for diseases involving abnormal DNA methylation, such as myelodysplastic syndrome (MDS) acute leukemia (AML), the methylation status remains unknown due to lack animal models difficulty obtaining patient-derived samples. Results Using genome editing techniques, we established two lines human induced pluripotent stem cells (iPSCs) different FPDMM-mimicking mutations. The iPSCs showed defective differentiation hematopoietic progenitor (HPCs) megakaryocytes (Mks), consistent FPDMM. HPCs differentiated from patterns distinct those wild-type HPCs. Binding motif-enrichment analysis enrichment ETS transcription factor (TF) motifs hypermethylated regions, contrast motif. We found that expression FLI1 , family member, was significantly downregulated mutation transactivation domain (TAD) RUNX1. demonstrated promoted binding-site-directed demethylation, overexpression HPC TAD restored their Mk efficiency hypermethylation status. Conclusion These results suggested putative causative TF responsible differential presence Thus, this study provided insights into part pathogenesis

Language: Английский

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