ROLE OF GLUCOCORTICOIDS IN MYELOID LEUKEMIA CELL DIFFERENTIATION INDUCED BY RETINOIC ACID

MICAELA SILBERMINS; ADALI PECCI; LUCIANA ROCHA VIEGAS

Congreso; Reunión Conjunta de Sociedades de Biociencias; 2017

The leukemias are malignant diseases of hematopoieticcells in which the proper balance between proliferation, differentiation andapoptosis is no longer operative. Synthetic glucocorticoids like dexametasone(Dex) are frequently used in the treatment of hematopoietic diseases due to itspro-apoptotic properties. On the other hand, in many clinical trials thedifferentiation inducer retinoic acid (RA) resulted not encouraging in mostmyeloid patients. In this sense, our hypothesis suggests that a combination ofsteroid hormones and RA could represent an alternative and promising therapy.The main goal of this project is to study the role of glucocorticoids in RA-inducedhuman promyelocytic leukemia cell differentiation. Undifferentiated NB4 cellswere treated with RA in the presence or absence of Dex over 72h. Our resultsshowed that Dex markedly enhances a RA-induced cell differentiation response,observed as a potentiated expression of the cell surface marker CD11c by flowcytometry analysis (control: (0±1)% RA: (19±2)% RA+Dex: (54±3)% - p≤0.01). Togain functional insights into this differentiation process, the expression of hoxgenes, pscd4, meis2, gr and rarβ was monitored inRT-qPCR assays. Notably, upon 48h, the addition of Dex potentiates RA-inducedexpression of hoxA3 (p≤0.02) and pscd4 (p≤0.05) genes. Finally,PML-RARα and RARα protein down-regulation upon RA stimulation was confirmed bywestern blot, and remained unchanged upon combined treatment with Dex. Overall,our data reveals the existence of a synergistic effect of Dex and RA on NB4cell differentiation. Further characterization of this molecular context couldaid to identify attractive targets for therapeutic strategies in myeloidleukemia.<!-- /* Font Definitions */@font-face{font-family:Arial;panose-1:2 11 6 4 2 2 2 2 2 4;mso-font-charset:0;mso-generic-font-family:auto;mso-font-pitch:variable;mso-font-signature:-536859905 -1073711037 9 0 511 0;}@font-face{font-family:Times;panose-1:2 0 5 0 0 0 0 0 0 0;mso-font-charset:0;mso-generic-font-family:auto;mso-font-pitch:variable;mso-font-signature:3 0 0 0 1 0;}@font-face{font-family:"ＭＳ 明朝";mso-font-charset:78;mso-generic-font-family:auto;mso-font-pitch:variable;mso-font-signature:-536870145 1791491579 18 0 131231 0;}@font-face{font-family:"ＭＳ 明朝";mso-font-charset:78;mso-generic-font-family:auto;mso-font-pitch:variable;mso-font-signature:-536870145 1791491579 18 0 131231 0;}@font-face{font-family:Calibri;panose-1:2 15 5 2 2 2 4 3 2 4;mso-font-charset:0;mso-generic-font-family:auto;mso-font-pitch:variable;mso-font-signature:-520092929 1073786111 9 0 415 0;}@font-face{font-family:Cambria;panose-1:2 4 5 3 5 4 6 3 2 4;mso-font-charset:0;mso-generic-font-family:auto;mso-font-pitch:variable;mso-font-signature:-536870145 1073743103 0 0 415 0;} /* Style Definitions */p.MsoNormal, li.MsoNormal, div.MsoNormal{mso-style-unhide:no;mso-style-qformat:yes;mso-style-parent:"";margin-top:0cm;margin-right:0cm;margin-bottom:10.0pt;margin-left:0cm;line-height:115%;mso-pagination:widow-orphan;font-size:11.0pt;font-family:Calibri;mso-fareast-font-family:Calibri;mso-bidi-font-family:"Times New Roman";mso-ansi-language:EN-US;mso-fareast-language:EN-US;}.MsoChpDefault{mso-style-type:export-only;mso-default-props:yes;font-size:10.0pt;mso-ansi-font-size:10.0pt;mso-bidi-font-size:10.0pt;font-family:Cambria;mso-ascii-font-family:Cambria;mso-fareast-font-family:"ＭＳ 明朝";mso-hansi-font-family:Cambria;}@page WordSection1{size:612.0pt 792.0pt;margin:70.85pt 3.0cm 70.85pt 3.0cm;mso-header-margin:36.0pt;mso-footer-margin:36.0pt;mso-paper-source:0;}div.WordSection1{page:WordSection1;}-->