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

被引：46

作者：

Esteghamat, Fatemehsadat ^{[1
]}

Gillemans, Nynke ^{[1
]}

Bilic, Ivan ^{[2
]}

van den Akker, Emile ^{[3
]}

Cantu, Ileana ^{[1
]}

van Gent, Teus ^{[1
,4
]}

Klingmueller, Ursula ^{[5
]}

van Lom, Kirsten ^{[6
]}

von Lindern, Marieke ^{[3
]}

Grosveld, Frank ^{[1
,4
,7
]}

van Dijk, Thamar Bryn ^{[1
]}

Busslinger, Meinrad ^{[2
]}

Philipsen, Sjaak ^{[1
]}

机构：

[1] Erasmus MC, Dept Cell Biol, NL-3000 CA Rotterdam, Netherlands

[2] Res Inst Mol Pathol, A-1030 Vienna, Austria

[3] Sanquin Res Dept Hematopoiesis, Amsterdam, Netherlands

[4] Erasmus MC, Netherlands Consortium Syst Biol, NL-3000 CA Rotterdam, Netherlands

[5] German Canc Res Ctr, Heidelberg, Germany

[6] Erasmus MC, Dept Hematol, NL-3000 CA Rotterdam, Netherlands

[7] Erasmus MC, Ctr Biomed Genet, NL-3000 CA Rotterdam, Netherlands

来源：

BLOOD | 2013年 / 121卷 / 13期

基金：

欧洲研究理事会;

关键词：

KRUPPEL-LIKE FACTOR; FACTOR KLF1 CAUSES; FETAL-HEMOGLOBIN; GENE-EXPRESSION; GAMMA-GLOBIN; ERYTHROID-DIFFERENTIATION; BETA-THALASSEMIA; TRANSGENIC MICE; MOLECULAR-BASIS; EKLF;

D O I：

10.1182/blood-2012-06-434530

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

B-cell lymphoma 11A (BCL11A) downregulation in human primary adult erythroid progenitors results in elevated expression of fetal gamma-globin. Recent reports showed that BCL11A expression is activated by KLF1, leading to gamma-globin repression. To study regulation of erythropoiesis and globin expression by KLF1 and BCL11A in an in vivo model, we used mice carrying a human beta-globin locus transgene with combinations of Klf1 knockout, Bcl11a floxed, and EpoR(Cre) knockin alleles. We found a higher percentage of reticulocytes in adult Klf1(wt/ko) mice and a mild compensated anemia in Bcl11a(cko/cko) mice. These phenotypes were more pronounced in compound Klf1(wt/ko):: Bcl11a(cko/cko) mice. Analysis of Klf1(wt/ko), Bcl11a(cko/cko), and Klf1(wt/ko)::Bcl11a(cko/cko) mutant embryos demonstrated increased expression of mouse embryonic globins during fetal development. Expression of human gamma-globin remained high in Bcl11a(cko/cko) embryos during fetal development, and this was further augmented in Klf1(wt/ko) :: Bcl11a(cko/cko) embryos. After birth, expression of human gamma-globin and mouse embryonic globins decreased in Bcl11a(cko/cko) and Klf1(wt/ko):: Bcl11a(cko/cko) mice, but the levels remained much higher than those observed in control animals. Collectively, our data support an important role for the KLF1-BCL11A axis in erythroid maturation and developmental regulation of globin expression.

引用

页码：2553 / 2562

页数：10

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