Abstract 5162

We provide additional data on members of the family from Malta with Hereditary Persistence of Fetal Hemoglobin (HPFH) due to KLF1 haplo-insufficiency. The data indicated a possible role of additional loci in the pathway of globin gene control. We showed that KLF1 functions as a master regulator of erythropoiesis and developmental globin gene switching (Borg et al., Nature Genetics doi: 10. 1038/ng.630, 2010), at least partly through BCL11A. Given the phenoytpes of the HPFH heterozygotes, the truncating KLF1 p.K288X was best described as a dominant mutation with variable penetrance; most likely due to interplay with other regulatory factors that we have been seeking.

Genome-wide association analysis, in the context of genome-wide expression profiles from cultured Human Erythroid Progenitors (HEPs) of critically informative family members, revealed additional loci of potential interest.

The effect of the Hb F inducer Hydroxyurea on the gamma globin profiles of the KLF1- (p.K288X) HPFH HEPs was enhanced compared to the wild type, and 74 loci were differentially expressed.

It is anticipated that extensive re-sequencing of these new targets may reveal the extent of the molecular pathways under control of KLF1 in erythropoiesis and globin gene switching, and in particular those that may be targeted for therapeutics in patients.

Disclosures:

No relevant conflicts of interest to declare.

Topics:
genes, switch, globins, fetal hemoglobin, gamma-globins, hereditary persistence of fetal hemoglobin, hydroxyurea, erythroid progenitor cells, malta
*

Asterisk with author names denotes non-ASH members.

© 2010 by The American Society of Hematology
2010
Sign in via your Institution