Deregulation of polycomb repressor complex 1 modifier AUTS2 in T-cell leukemia.
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.
Department of Human and Animal Cell Lines, Leibniz-Institute DSMZ - German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany.
Stefan
S
Nagel
Department of Human and Animal Cell Lines, Leibniz-Institute DSMZ - German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany.
Claudia
C
Pommerenke
Department of Human and Animal Cell Lines, Leibniz-Institute DSMZ - German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany.
Corinna
C
Meyer
Department of Human and Animal Cell Lines, Leibniz-Institute DSMZ - German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany.
Maren
M
Kaufmann
Department of Human and Animal Cell Lines, Leibniz-Institute DSMZ - German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany.
Hans G
HG
Drexler
Department of Human and Animal Cell Lines, Leibniz-Institute DSMZ - German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany.
Roderick A F
RA
MacLeod
D045744:Cell Line, Tumor; D003598:Cytoskeletal Proteins; D053263:Gene Regulatory Networks; D006801:Humans; D064326:MEF2 Transcription Factors / Q000502:physiology; D051957:MSX1 Transcription Factor / Q000235:genetics; D063150:Polycomb Repressive Complex 1 / Q000502:physiology*; D063151:Polycomb Repressive Complex 2 / Q000502:physiology*; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D011506:Proteins / Q000502:physiology*; D050799:STAT5 Transcription Factor / Q000502:physiology; D014157:Transcription Factors
C554283:AUTS2 protein, human; D003598:Cytoskeletal Proteins; D064326:MEF2 Transcription Factors; C578040:MEF2C protein, human; D051957:MSX1 Transcription Factor; C484083:MSX1 protein, human; D011506:Proteins; D050799:STAT5 Transcription Factor; D014157:Transcription Factors; D063151:Polycomb Repressive Complex 2; D063150:Polycomb Repressive Complex 1
IL-7; IL7R; MEF2C; PRC1; PRC2