KLF10 gene expression is associated with high fetal hemoglobin levels and with response to hydroxyurea treatment in β-hemoglobinopathy patients.
OBJECTIVE
In humans, fetal hemoglobin (HbF) production is controlled by many intricate mechanisms that, to date, remain only partly understood.


METHODS
Pharmacogenomic analysis of the effects of hydroxyurea (HU) on HbF production was undertaken in a collection of Hellenic β-thalassemia and sickle cell disease (SCD) compound heterozygotes and a collection of healthy and KLF1-haploinsufficient Maltese adults, to identify genomic signatures that follow high HbF patterns.


RESULTS
KLF10 emerged as a top candidate. Moreover, genotype analysis of β-thalassemia major and intermedia patients and an independent cohort of β-thalassemia/SCD compound heterozygous patients that do or do not respond to HU treatment showed that the homozygous mutant state of a tagSNP in the KLF10 3'UTR is not present in β-thalassemia intermedia patients and is underrepresented in β-thalassemia/SCD compound heterozygous patients that respond well to HU treatment.


CONCLUSIONS
These data suggest that KLF10 may constitute a pharmacogenomic marker to discriminate between response and nonresponse to HU treatment.
Erasmus University Medical Center, Department of Cell Biology, Rotterdam, The Netherlands.
Joseph
J
Borg
Marios
M
Phylactides
Marina
M
Bartsakoulia
Christina
C
Tafrali
Carsten
C
Lederer
Alexander E
AE
Felice
Adamantia
A
Papachatzopoulou
Alexandra
A
Kourakli
Eleana F
EF
Stavrou
Soteroula
S
Christou
Jun
J
Hou
Sophia
S
Karkabouna
Christina
C
Lappa-Manakou
Zeliha
Z
Ozgur
Wilfred
W
van Ijcken
Marieke
M
von Lindern
Frank G
FG
Grosveld
Marianthi
M
Georgitsi
Marina
M
Kleanthous
Sjaak
S
Philipsen
George P
GP
Patrinos
D020413:3' Untranslated Regions; D000328:Adult; D000755:Anemia, Sickle Cell / Q000097:blood / Q000188:drug therapy / Q000235:genetics; D000986:Antisickling Agents / Q000627:therapeutic use; D051765:Early Growth Response Transcription Factors / Q000235:genetics*; D015672:Erythroid Precursor Cells / Q000378:metabolism; D005260:Female; D005319:Fetal Hemoglobin / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D005819:Genetic Markers; D006453:Hemoglobinopathies / Q000097:blood / Q000188:drug therapy* / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D006918:Hydroxyurea / Q000627:therapeutic use*; D051741:Kruppel-Like Transcription Factors / Q000235:genetics*; D008297:Male; D020641:Polymorphism, Single Nucleotide; D012189:Retrospective Studies; D059467:Transcriptome; D017086:beta-Thalassemia / Q000097:blood / Q000188:drug therapy / Q000235:genetics
D020413:3' Untranslated Regions; D000986:Antisickling Agents; D051765:Early Growth Response Transcription Factors; D005819:Genetic Markers; C098111:KLF10 protein, human; D051741:Kruppel-Like Transcription Factors; D005319:Fetal Hemoglobin; D006918:Hydroxyurea