MYB-ETS FUSION ONCOPROTEIN INHIBITS THYROID-HORMONE RECEPTOR C-ERBA AND RETINOIC ACID RECEPTOR FUNCTIONS - A NOVEL MECHANISM OF ACTION FOR LEUKEMOGENIC TRANSFORMATION BY E26 AVIAN RETROVIRUS/

The E26 and avian erythroblastosis virus (AEV) avian retroviruses indu ce acute leukemia in chickens, E26 can block both erythroid and myeloi d differentiation at an early multipotent stage, Moreover, E26 can blo ck erythroid differentiation at the erythroid burst-forming unit/eryth roid CFU (BFU-E/CFU-E) stage, which also corresponds to the differenti ation stage blocked by AEV. AEV carries two oncogenes, v-erbA and v-er bB, whereas E26 encodes a single 135-kDa Gag-Myb-Ets fusion oncoprotei n. v-ErbA is responsible for the erythroid differentiation arrest thro ugh negative interferences with both the retinoic acid receptor (RAR) and the thyroid hormone receptor (T3R/c-ErbA). We investigated whether Myb-Ets could block erythroid differentiation in a manner similar to v-ErbA, We show here that Myb-Ets inhibits both RAR and c-ErbA activit ies on specific hormone response elements in transient-expression assa ys. Moreover, Myb-Ets abrogates the inactivation of transcription fact or, AP-1 by RAR and T3R, another feature shared with v-ErbA. Myb-Ets a lso antagonizes the biological response of erythrocytic progenitor cel ls to retinoic acid and T3. Analysis of a series of mutants of Myb-Ets reveals that the domains of the oncoprotein involved in these inhibit ory activities are the same as those involved in oncogenic transformat ion of hematopoietic cells, These data demonstrate that the Myb-Ets on coprotein shares properties with the v-ErbA oncoprotein and that inhib ition of ligand-dependent RAR and c-ErbA functions bg Myb-Ets is respo nsible for blocking the differentiation of hematopoietic progenitors.