YY1 Knockdown Relieves the Differentiation Block and Restores Apoptosis in AML Cells

Acute myeloid leukemia (AML) is characterized by the expansion of clonally derived hematopoietic precursors undergoing a partial or complete maturation block. De novo AML is characterized by recurrent cytogenetic alterations such as chromosomal translocations. However, in the recent past, it was shown that several somatic mutations and epigenetic alterations also contribute to AML onset and progression. Epigenetic mechanisms regulate the equilibrium between self-renewal and differentiation of hematopoietic stem cells and precursors. In this context, Polycomb-group (PcG) proteins regulate the expression of genes involved in cell-cycle regulation and differentiation, and aberrant expression and/or mutations of PcG genes have been shown to occur in hematopoietic neoplasms.In this study we analyzed the expression of Yin and Yang 1 protein (YY1), a member of the noncanonical PcG complexes, in AML patient samples and AML cell lines and the effect of YY1 downregulation on the AML differentiation block. Our results show that YY1 is significantly overexpressed in AML patient samples and AML cell lines and that YY1 knockdown relieves the differentiation block. YY1 downregulation in two AML cell lines (HL-60 and OCI-AML3) and one AML patient sample restored the expression of members of the CEBP protein family, increased the expression of extrinsic growth factors/receptors and surface antigenic markers, induced morphological cell characteristics typical of myeloid differentiation, and sensitized cells to retinoic acid treatment and to apoptosis. Overall, our data show that YY1 is not a secondary regulator of myeloid differentiation but that, if overexpressed, it can play a predominant role in myeloid differentiation block.