Role of glucocorticoid receptor in cell death and differentiation in myeloid leukemia

ADALI PECCI; LUCIANA ROCHA VIEGAS; MICAELA SILBERMINS

Heidelberg

Conferencia; Transcription and Chromatin, EMBL Conference; 2018

EMBL

The leukemias are malignant diseases of hematopoietic cells in which the proper balance between proliferation, differentiation and apoptosis is no longer operative. Targeting the apoptosis machinery is a promising therapeutic approach in myeloid malignancies. Bcl-x is a well-known glucocorticoid-responsive gene and a key apoptosis regulator that, when over-expressed can contribute to tumour development, progression and therapeutic resistance. Moreover, synthetic glucocorticoids, like dexamethasone (Dex), are frequently used in the treatment of hematopoietic diseases due to its pro-apoptotic properties. We report here that ligand-independent glucocorticoid receptor (GR) and the trithorax protein ASH2L are both recruited to bcl-X gene in human myeloid leukemic cells, contributing to anti-apoptotic bcl-XL over-expression. Furthermore, glucocorticoids inhibit GR and ASH2L binding to chromatin, affect bcl-XL expression and consequently induce apoptosis. On the other hand, in many clinical trials the differentiation inducer retinoic acid (RA) results not encouraging in most myeloid patients. In this sense, our hypothesis suggests that a combination of steroid hormones and RA could represent an alternative and promising therapy. The main goal of this second part is to study the role of glucocorticoids in RA-induced human promyelocytic leukemia (APL) cell differentiation. Our results showed that Dex markedly enhances a RA-induced NB4 cell differentiation response and notably potentiates RA-induced expression of hoxA3, hoxA4 and pscd4 genes. Overall, our findings highlight, on one hand, the significance of ASH2L in promoting leukemia cell death inhibition through ligand-independent GR association to bcl-X promoter region. On the other hand, our data reveals the existence of a potentiated effect of Dex and RA on NB4 cell differentiation. Further characterization of these molecular contexts could aid to identify attractive targets for therapeutic strategies in myeloid leukemia.