Development and characterization of K562 cell clones expressing BCL11A-XL: Decreased hemoglobin production with fetal hemoglobin inducers and its rescue with mithramycin.

Abstract:

:Induction of fetal hemoglobin (HbF) is considered a promising strategy in the treatment of β-thalassemia, in which production of adult hemoglobin (HbA) is impaired by mutations affecting the β-globin gene. Recent results indicate that B-cell lymphoma/leukemia 11A (BCL11A) is a major repressor of γ-globin gene expression. Therefore, disrupting the binding of the BCL11A transcriptional repressor complex to the γ-globin gene promoter provides a novel approach for inducing expression of the γ-globin genes. To develop a cellular screening system for the identification of BCL11A inhibitors, we produced K562 cell clones with integrated copies of a BCL11A-XL expressing vector. We characterized 12 K562 clones expressing different levels of BCL11A-XL and found that a clear inverse relationship does exist between the levels of BCL11A-XL and the extent of hemoglobinization induced by a panel of HbF inducers. Using mithramycin as an inducer, we found that this molecule was the only HbF inducer efficient in rescuing the ability to differentiate along the erythroid program, even in K562 cell clones expressing high levels of BCL11A-XL, suggesting that BCL11A-XL activity is counteracted by mithramycin.

journal_name

Exp Hematol

journal_title

Experimental hematology

authors

Finotti A,Gasparello J,Breveglieri G,Cosenza LC,Montagner G,Bresciani A,Altamura S,Bianchi N,Martini E,Gallerani E,Borgatti M,Gambari R

doi

10.1016/j.exphem.2015.08.011

subject

Has Abstract

pub_date

2015-12-01 00:00:00

pages

1062-1071.e3

issue

12

eissn

0301-472X

issn

1873-2399

pii

S0301-472X(15)00658-X

journal_volume

43

pub_type

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