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

Experimental Hematology
Alessia FinottiRoberto Gambari

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.

References

Sep 1, 1979·Proceedings of the National Academy of Sciences of the United States of America·R GambariR A Rifkind
Jun 29, 2000·Baillière's Clinical Haematology·D J Weatherall
Aug 22, 2003·European Journal of Haematology·Ilaria LamprontiRoberto Gambari
Nov 11, 2008·Current Molecular Medicine·Jennifer G Michlitsch, Mark C Walters
Oct 8, 2009·Human Molecular Genetics·Swee Lay TheinChad Garner
Nov 16, 2010·Hematology/oncology Clinics of North America·George Atweh, Hassana Fathallah
Nov 19, 2010·Expert Review of Hematology·Roshan ColahAnita Nadkarni
Mar 15, 2012·Expert Opinion on Biological Therapy·Roberto Gambari
Oct 19, 2013·Nucleic Acids Research·Belinda GiardineGeorge P Patrinos
Mar 5, 2014·Hematology/oncology Clinics of North America·Susan P PerrineDouglas V Faller
Jun 18, 2014·Expert Opinion on Biological Therapy·Alessia Finotti, Roberto Gambari
Aug 6, 2014·Nucleic Acids Research·Junyi JuQuan Zhao
Jun 18, 2015·Molecular Therapy : the Journal of the American Society of Gene Therapy·Swaroopa GudaDavid A Williams

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Citations

Dec 1, 2017·International Journal of Molecular Sciences·Jessica GasparelloAlessia Finotti
Oct 28, 2019·Bioscience Reports·Jiawei YinFengyuan Che

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Methods Mentioned

BETA
transgenic
fluorescence-activated cell sorting
FACS
electrophoretic mobility shift assay

Software Mentioned

GraphPad Prism

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