Erythropoiesis and globin switching in compound Klf1::Bcl11a mutant mice

Abstract

Key Points• Our data support an important role for the KLF1-BCL11A axis in erythroid maturation and hemoglobin switching.• In adults, gamma-globin levels decline in Bcl11a and Klf1::Bcl11a mutants, suggesting an additional layer of gamma-globin silencing.

Induction of adult levels of -globin in human erythroid cells that intrinsically express embryonic or fetal globin by transduction with KLF1 and BCL11A-XL

“…41 A KLF1-BCL11A axis has also been described for compound KLF1::BCL11A mutant mice carrying a human β-globin locus transgene, with repression of γ-globin expression. 42 However, although KLF1 positively regulates the expression of BCL11A in adult erythroid cells, increasing the level of KLF1 in K562 and cord blood cells did not result in an increase in BCL11A. Similarly, HiDEP-1 cells, which have levels of KLF1 similar to adult cells, do not express BCL11A.…”

Mutations in Krüppel-like factor 1 cause transfusion-dependent hemolytic anemia and persistence of embryonic globin gene expression

“…30 It is thought that this mutation acts as a dominant negative, gain-of-function mutation. In contrast, the patients described here have newly defined phenotypes (severe thalassemia or CNSHA) associated with KLF1 mutations.…”

“…3,4 Following on from observations of the effect of BCL11A deficiency on embryonic globin expression in the mouse 30 and the anecdotal observation that embryonic expression is increased in a patient with congenital dyserythropoietic anemia type IV associated with a dominantly acting KLF1 mutation (E325K), 30 it seems plausible that when KLF1 is downregulated to a critical level, it also has a similar effect on human embryonic globin expression.…”

An Erythroid Enhancer of BCL11A Subject to Genetic Variation Determines Fetal Hemoglobin Level

“…GWAS of HbF level have identified trait-associated variants at BCL11A (7–12) (see supplementary online text). The transcriptional repressor BCL11A has been validated as a direct regulator of HbF level (13–18). Although constitutive BCL11A deficiency results in embryonic lethality and impaired lymphocyte development (19, 20), erythroid-specific deficiency of BCL11A counteracts developmental silencing of embryonic and fetal globin genes and rescues the hematologic and pathologic features of sickle cell disease (SCD) in mouse models (17).…”