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

AuthorsRocha-Viegas, Luciana; Silberminsa, Micaela; Ogara, Maria F.; Pellegrini, Joaquín Miguel; Yanel Nuñez, Sol; García, Verónica Edith; Vicent, Guillermo P.; Pecci, Adali
KeywordsGlucocorticoid receptor
BCL2L1 gene
Myeloid leukemia
Issue Date2020
CitationBiochimica et Biophysica Acta - Gene Regulatory Mechanisms 1863: 194475 (2020)
AbstractTargeting 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.
Publisher version (URL)https://doi.org/10.1016/j.bbagrm.2019.194475
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