Format

Send to

Choose Destination
Biochim Biophys Acta Gene Regul Mech. 2020 Jan;1863(1):194475. doi: 10.1016/j.bbagrm.2019.194475. Epub 2019 Dec 20.

Glucocorticoids uncover a critical role for ASH2L on BCL-X expression regulation in leukemia cells.

Author information

1
CONICET-Universidad de Buenos Aires, Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE), C1428EHA, Buenos Aires, Argentina. Electronic address: lrochav@qb.fcen.uba.ar.
2
CONICET-Universidad de Buenos Aires, Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE), C1428EHA, Buenos Aires, Argentina.
3
CONICET-Universidad de Buenos Aires, Instituto de Química Biológica Ciencias Exactas y Naturales (IQUIBICEN), C1428EHA, Buenos Aires, Argentina; Universidad de Buenos Aires, Facultad de Ciencias Exactas y Naturales, Departamento de Química Biológica, C1428EHA, Buenos Aires, Argentina.
4
Laboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biología y Medicina Experimental (IBYME-CONICET), C1428ADN, Buenos Aires, Argentina.
5
Department of Molecular Genomics, Molecular Biology Institute of Barcelona (IBMB-CSIC), Baldiri Reixac 4-8, 08028, Barcelona, Spain.
6
CONICET-Universidad de Buenos Aires, Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE), C1428EHA, Buenos Aires, Argentina; Universidad de Buenos Aires, Facultad de Ciencias Exactas y Naturales, Departamento de Química Biológica, C1428EHA, Buenos Aires, Argentina.

Abstract

Targeting the apoptosis machinery is a promising therapeutic approach in myeloid malignancies. BCL2L1 is a well-known glucocorticoid-responsive gene and a key apoptosis regulator that, when over-expressed, can contribute to tumor development, progression and therapeutic resistance. Moreover, synthetic glucocorticoids, like dexamethasone, are frequently used in the treatment of hematopoietic diseases due to its pro-apoptotic properties. We report here that the trithorax protein ASH2L, considered one of the core subunits of H3K4-specific MLL/SET methyltransferase complexes, contributes to anti-apoptotic BCL-XL over-expression and cell survival in patient-derived myeloid leukemia cells. We find that the unliganded glucocorticoid receptor (uGR) and ASH2L interact in a common protein complex through a chromatin looping determined by uGR and ASH2L binding to BCL2L1 specific +58 HRE and promoter region, respectively. Upon addition of dexamethasone, GR and ASH2L recruitment is reduced, BCL-XL expression diminishes and apoptosis is induced consequently. Overall, our findings indicate that uGR and ASH2L may act as key regulatory players of BCL- XL upregulation in AML cells.

KEYWORDS:

ASH2L; BCL2L1 gene; Glucocorticoid receptor; Myeloid leukemia

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center