Abstract Abstract 1281 Poster Board I-303 Many oncogenes code for transcription factors involved in regulation of developmental pathways. The activity of these pathways is tissue specific and restricted to certain developmental stages. Here, we searched for T-cell acute lymphoblastic leukemia (T-ALL) oncogenes which physiologically regulate differentiation of natural killer (NK) cells. NK- and T-cells are closely related lymphocytes, sharing the same early progenitors which can differentiate into either lineage. We compared expression profiles of malignant NK- and T-cell lines to identify aberrantly expressed genes in T-ALL. This analysis revealed high expression of HOXA9, HOXA10 and ID2 in NK-cell lines and in one T-ALL line, LOUCY, suggesting leukemic deregulation therein. Subsequently, we analyzed mechanisms underlying their regulation. Overexpression and chromatin immuno-precipitation experiments demonstrated that HOXA9 and HOXA10 directly activate ID2 expression. Analysis of other ALL and acute myeloid leukemia cell lines with and without mixed lineage leukemia (MLL) gene translocations demonstrated a correlated expression of HOXA9/10 and ID2, highlighting ID2 as an indirect target of MLL fusion proteins which deregulate HOXA genes. Furthermore, profiling data of genes coding for chromatin regulators of homeobox genes, including the components EZH2 and HOP of polycomb repressor complex 2 (PRC2), showed downregulation of EZH2 in LOUCY and limited expression of HOP to NK-cell lines. Subsequent treatment of T-ALL cell lines JURKAT and LOUCY with DZNep, an inhibitor of EZH2/PRC2, resulted in elevated and unchanged HOXA9/10 expression levels, respectively, confirming repressive activity of EZH2 in T-cells. Additionally, profiling data and overexpression analysis indicated that reduced expression of E2F cofactor TFDP1 contributed to the lack of EZH2 in LOUCY. Forced expression of HOP in JURKAT cells resulted in reduced HOXA10 and ID2 expression levels, suggesting enhancement of PRC2 repression. Taken together, our results show that major differentiation factors of the NK-cell lineage, including HOXA9, HOXA10 and ID2, were (de)regulated via PRC2 and may contribute to T-cell leukemogenesis. Disclosures No relevant conflicts of interest to declare.