INTERNATIONAL CONGRESS OF
CancerGenetics
Epigenetic Reactivation of Fetal Hemoglobin in Leukemia: A Mechanism of Clonal Advantage
-
Ali Zarei,1,*
1. Department of Human Genetics, Iranian Academic Center for Education, Culture and Research (ACECR)-Fars Branch Institute for Human Genetics Research, Shiraz, Iran
- Introduction: Acquired fetal hemoglobin (HbF) expression is observed in acute erythroid leukemia (AEL) and myelodysplastic syndromes (MDS). We investigated the hypothesis that epigenetic dysregulation, not genetic mutation, is the primary driver of this ontogenic reversal in malignancy.
- Methods: A systematic literature review was conducted to synthesize evidence on epigenetic mechanisms behind somatic HbF reactivation in hematologic cancers.
- Results: The review identifies that breakdown of the native epigenetic repressor complex—involving BCL11A, ZBTB7A, and DNMTs—is a key event. This occurs via somatic promoter hypomethylation of the HBG genes and loss of repressive histone marks (e.g., H3K27me3) in malignant clones, leading to HbF derepression. This phenotype is associated with enhanced clonal fitness and poor risk disease.
- Conclusion: Epigenetic reactivation of HbF is a selected trait in leukemogenesis. It likely confers a survival advantage through improved oxidative stress resistance, contributing to chemoresistance. Targeting this epigenetic machinery represents a promising therapeutic strategy for HbF-positive malignancies.
- Keywords: Fetal Hemoglobin, Epigenetics, Leukemia, BCL11A, DNA Methylation
