Abstract
Recently, we identified deregulated expression of the B-cell specific transcription factor MEF2C in T-cell acute lymphoid leukemia (T-ALL). Here, we performed sequence analysis of a regulatory upstream section of MEF2C in T-ALL cell lines which, however, proved devoid of mutations. Unexpectedly, we found strong conservation between the regulatory upstream region of MEF2C (located at chromosomal band 5q14) and an intergenic stretch at 7q11 located between STAG3L4 and AUTS2, covering nearly 20 kb. While the non-coding gene STAG3L4 was inconspicuously expressed, AUTS2 was aberrantly upregulated in 6% of T-ALL patients (public dataset GSE42038) and in 3/24 T-ALL cell lines, two of which represented very immature differentiation stages. AUTS2 expression was higher in normal B-cells than in T-cells, indicating lineage-specific activity in lymphopoiesis. While excluding chromosomal aberrations, examinations of AUTS2 transcriptional regulation in T-ALL cells revealed activation by IL7-IL7R-STAT5-signalling and MEF2C. AUTS2 protein has been shown to interact with polycomb repressor complex 1 subtype 5 (PRC1.5), transforming this particular complex into an activator. Accordingly, expression profiling and functional analyses demonstrated that AUTS2 activated while PCGF5 repressed transcription of NKL homeobox gene MSX1 in T-ALL cells. Forced expression and pharmacological inhibition of EZH2 in addition to H3K27me3 analysis indicated that PRC2 repressed MSX1 as well. Taken together, we found that AUTS2 and MEF2C, despite lying on different chromosomes, share strikingly similar regulatory upstream regions and aberrant expression in T-ALL subsets. Our data implicate chromatin complexes PRC1/AUTS2 and PRC2 in a gene network in T-ALL regulating early lymphoid differentiation.
Highlights
In T-cell acute lymphoid leukemia (T-ALL) several types of oncogenes are involved in leukemogenesis deregulating survival, proliferation and developmental processes, resulting in differentiation arrest of developing T-cells at particular stages [1,2,3]
We showed that copy number gain, IL7-STAT5-signalling, and transcription factors (TFs) MEF2C contribute to the aberrant expression of AUTS2 in T-ALL
We focused on MSX1 and HOXA10 previously described as aberrantly expressed in earlystaged T-ALL and which are regulated by chromatin modifications [9, 13, 18]
Summary
In T-cell acute lymphoid leukemia (T-ALL) several types of oncogenes are involved in leukemogenesis deregulating survival, proliferation and developmental processes, resulting in differentiation arrest of developing T-cells at particular stages [1,2,3]. Aberrant activation of NKL homeobox gene MSX1 is not mediated by chromosomal alterations but via deregulation of the BMP-signalling pathway [9]. This gene is physiologically expressed in early lymphopoiesis and silenced during ensuing differentiation steps [10]. Aberrant activation of MEF2C during T-cell differentiation contributes to leukemogenesis in a subset of T-ALL associated with an immature phenotype [26, 27] In this malignant context MEF2C transcription is directly activated by the oncogenic TF NKX2-5 or via chromosomal aberrations including T-cell receptor gene translocation or upstream deletion. Subsequent investigations revealed novel roles for AUTS2 as chromatin modulator impacting early lymphoid development and T-cell leukemogenesis
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