Epigenetic dysregulation of the erythropoietic transcription factor KLF1 and the β-like globin locus in juvenile myelomonocytic leukemia

Abstract

Increased levels of fetal hemoglobin (HbF) are a hallmark of more than half of the children diagnosed with juvenile myelomonocytic leukemia (JMML). Elevated HbF levels in JMML are associated with DNA hypermethylation of distinct gene promoter regions in leukemic cells. Since the regulation of globin gene transcription is known to be under epigenetic control, we set out to study the relation of DNA methylation patterns at β-/γ-globin promoters, mRNA and protein expression of globins, and epigenetic modifications of genes encoding the globin-regulatory transcription factors BCL11A and KLF1 in nucleated erythropoietic precursor cells of patients with JMML. We describe several altered epigenetic components resulting in disordered globin synthesis in JMML. We identify a cis-regulatory upstream KLF1 enhancer sequence as highly sensitive to DNA methylation and frequently hypermethylated in JMML. The data indicate that the dysregulation of β-like globin genes is a genuine attribute of the leukemic cell clone in JMML and involves mechanisms not taking part in the normal fetal-to-adult hemoglobin switch.

Keywords

• epigenetic regulation
• fetal hemoglobin
• juvenile myelomonocytic leukemia
• klf1