Deregulation of polycomb repressor complex 1 modifier AUTS2 in T-cell leukemia

Area of Science:

• * Molecular Biology
• * Genetics
• * Cancer Research

Background:

• * Deregulated expression of the B-cell transcription factor MEF2C was recently identified in T-cell acute lymphoid leukemia (T-ALL).
• * Sequence analysis of MEF2C's regulatory upstream region in T-ALL cell lines revealed no mutations.

Purpose of the Study:

• * To investigate conserved regulatory regions between MEF2C and other genes in T-ALL.
• * To elucidate the role of AUTS2 and its regulatory network in T-ALL pathogenesis.

Main Methods:

• * Sequence analysis of MEF2C regulatory regions.
• * Gene expression profiling in T-ALL cell lines and patient datasets (GSE42038).
• * Chromatin immunoprecipitation (H3K27me3) and functional assays involving gene expression modulation and pharmacological inhibition (EZH2).

Main Results:

• * Strong sequence conservation was found between MEF2C's upstream region and an intergenic region at 7q11 containing AUTS2.
• * AUTS2 was aberrantly upregulated in a subset of T-ALL patients and cell lines, with higher expression in normal B-cells than T-cells.
• * AUTS2 and MEF2C activate AUTS2 transcription via IL7-IL7R-STAT5 signaling. AUTS2 interacts with PRC1.5, converting it to an activator.
• * AUTS2 activates, while PCGF5 and PRC2 repress, MSX1 transcription in T-ALL cells, implicating these complexes in regulating early lymphoid differentiation.

Conclusions:

• * AUTS2 and MEF2C share conserved regulatory upstream regions and exhibit aberrant expression in T-ALL.
• * The AUTS2/PRC1.5 and PRC2 complexes play a role in a gene network that regulates early lymphoid differentiation in T-ALL.
• * Findings highlight a novel regulatory network involving AUTS2, MEF2C, and chromatin modifiers in T-ALL pathogenesis.