CONICET | Buscador de Institutos y Recursos Humanos

Theleukemias are malignant diseases of hematopoietic cells in which the properbalance between proliferation, differentiation and apoptosis is no longer operative.Synthetic glucocorticoids like dexametasone (Dex) are frequently used in thetreatment of hematopoietic diseases due to its pro-apoptotic properties. Previouslywe demonstrated that human U937 cells undergo significant cell death after Dextreatment, in correlation with the down-regulation of the anti-apoptoticisoform Bcl-XL, over-expressed in myeloid leukemia. On the otherhand, in many clinical trials the differentiation inducer retinoic acid (RA)resulted not encouraging in most myeloid patients. In this sense, ourhypothesis suggests that a combination of steroid hormones and RA couldrepresent an alternative and promising therapy. The main goal of this projectis to study the role of glucocorticoids in RA-induced human promyelocyticleukemia cell differentiation. Undifferentiated HL60 cells were treated with RAin the presence or absence of Dex over 72h. Our results showed that Dexmarkedly enhances a RA-induced cell differentiation response, observed as a potentiatedexpression of the cell surface marker CD11b by flow cytometry analysis(control: 1.54 % RA: 28.6 % RA+Dex: 38.1 %). To gain functional insights intothis differentiation process, the expression of hox genes, pscd4, meis2 and rarβ wasmonitored in RT-qPCR assays. Notably, upon 24h of combined treatment theup-regulation of hoxA3 expression wasobserved. Finally, the addition of Dex potentiates RA-induced expression of hoxA3 and pscd4 genes after 48h of treatment, and the expression of hoxA4 gene after 72h. Overall, our datareveals the existence of a synergistic effect of Dex and RA on HL60 celldifferentiation. Further characterization of this molecular context could thusbe instrumental in defining a general molecular mechanism that identifies attractivetargets for therapeutic strategies in myeloid leukemia.