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 UNCX, activated by epigenetic modifications in acute myeloid leukemia (AML). We found the ectopic activation of UNCX 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. UNCX 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. UNCX 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. UNCX-positive and -negative patients displayed significant differences in their gene expression profiles. An enrichment of genes involved in cell proliferation and differentiation, such as MAP2K1 and CCNA1, was revealed. Similar results were obtained in UNCX-transduced CD34+ cells, associated with low proliferation and differentiation arrest. Accordingly, we showed that UNCX expression characterizes leukemia cells at their early stage of differentiation, mainly M2 and M3 subtypes carrying wild-type NPM1. We also observed that UNCX expression significantly associates with an increased frequency of acute promyelocytic leukemia with PML-RARA and AML with t(8;21)(q22;q22.1); RUNX1-RUNX1T1 classes, according to the World Health Organization disease classification. In summary, our findings suggest a novel leukemogenic role of UNCX, associated with epigenetic modifications and with impaired cell proliferation and differentiation in AML.

Epigenetic mediated zinc finger protein 671 downregulation promotes cell proliferation and tumorigenicity in nasopharyngeal carcinoma by inhibiting cell cycle arrest

“…Local recurrence and distant metastasis are the major patterns of treatment failure in NPC. Most cancers are caused by accumulation of genomic or epigenetic alterations [ 19 – 24 ], and epigenetic alterations play an important role in the development of NPC [ 9 , 25 ]. Several studies have indicated that aberrantly methylated genes could serve as prognostic biomarkers for NPC [ 26 – 28 ].…”

Characterization of paralogous uncx transcription factor encoding genes in zebrafish

“…A central role in the repression of Uncx expression in the anterior somite is played by a complex regulatory network that involves the basic helix–loop–helix transcription factor Mesp2, its downstream co-repressor Ripply, the homeodomain transcription factor MEOX1, and a cross-negative regulation with the T-box protein Tbx18 (Takahashi et al, 2000, Takahashi et al, 2003, Takahashi et al, 2013; Nakajima et al, 2006; Farin et al, 2008; Skuntz et al, 2009; Yabe et al, 2016). Recently, cell type-specific epigenetic regulation of Uncx gene expression has been associated with axon guidance in C. elegans (Zheng et al, 2013) and with human leukemia (Daniele et al, 2017). It has been proposed that Uncx is implicated in cell cycle progression of neuronal progenitor cells, survival of olfactory epithelium and differentiation of dopaminergic neurons (Sammeta et al, 2010; Rabe et al, 2012).…”

Multi-Omics Marker Analysis Enables Early Prediction of Breast Tumor Progression

“…UNCX was another gene with distinct expression distribution between training and validation data. It is a homeobox transcription factor that has been associated with acute myeloid leukemia ( Daniele et al, 2017 ). MAMDC2 is a known tumor suppressor involved in glycosaminoglycan binding ( Lee et al, 2020 ), whereas NPIPB6 has not previously been associated with cancers to the best of our knowledge.…”