Epigenetically induced ectopic expression of UNCX impairs the proliferation and differentiation of myeloid cells

Abstract

We here describe a leukemogenic role of the homeobox gene <i>UNCX</i>, activated by epigenetic modifications in acute myeloid leukemia (AML). We found the ectopic activation of <i>UNCX</i> in a leukemia patient harboring a t(7;10)(p22;p14) translocation, in 22 of 61 of additional cases [a total of 23 positive patients out of 62 (37.1%)], and in 6 of 75 (8%) of AML cell lines. <i>UNCX</i> is embedded within a low-methylation region (canyon) and encodes for a transcription factor involved in somitogenesis and neurogenesis, with specific expression in the eye, brain, and kidney. <i>UNCX</i> expression turned out to be associated, and significantly correlated, with DNA methylation increase at its canyon borders based on data in our patients and in archived data of patients from The Cancer Genome Atlas. <i>UNCX</i>-positive and -negative patients displayed significant differences in their gene expression profiles. An enrichment of genes involved in cell proliferation and differentiation, such as <i>MAP2K1</i> and <i>CCNA1</i>, was revealed. Similar results were obtained in <i>UNCX</i>-transduced CD34⁺ cells, associated with low proliferation and differentiation arrest. Accordingly, we showed that <i>UNCX</i> expression characterizes leukemia cells at their early stage of differentiation, mainly M2 and M3 subtypes carrying wild-type <i>NPM1</i> We also observed that <i>UNCX</i> expression significantly associates with an increased frequency of acute promyelocytic leukemia with <i>PML-RARA</i> and AML with t(8;21)(q22;q22.1); <i>RUNX1-RUNX1T1</i> classes, according to the World Health Organization disease classification. In summary, our findings suggest a novel leukemogenic role of <i>UNCX</i>, associated with epigenetic modifications and with impaired cell proliferation and differentiation in AML.