The vascular bone marrow niche influences outcome in chronic myeloid leukemia via the E-selectin - SCL/TAL1 - CD44 axis.

The endosteal bone marrow niche and vascular endothelial cells provide sanctuaries for leukemic cells. In murine chronic myeloid leukemia (CML) CD44 on leukemia cells and E-selectin on bone marrow endothelium are essential mediators for the engraftment of leukemic stem cells. We hypothesized that non-adhesion of CML-initiating cells to E-selectin on the bone marrow endothelium may lead to superior eradication of leukemic stem cells in CML after treatment with imatinib than imatinib alone. Indeed, here we show that treatment with the E-selectin inhibitor GMI-1271 in combination with imatinib prolongs survival of mice with CML via decreased contact time of leukemia cells with bone marrow endothelium. Non-adhesion of BCR-ABL1+ cells leads to an increase of cell cycle progression and an increase of expression of the hematopoietic transcription factor and proto-oncogene Scl/Tal1 in leukemia-initiating cells. We implicate SCL/TAL1 as an indirect phosphorylation target of BCR-ABL1 and as a negative transcriptional regulator of CD44 expression. We show that increased SCL/TAL1 expression is associated with improved outcome in human CML. These data demonstrate the BCR-ABL1-specific, cell-intrinsic pathways leading to altered interactions with the vascular niche via the modulation of adhesion molecules - which could be exploited therapeutically in the future.

Prmt6 represses the pro-adipogenic Ppar-gamma-C/ebp-alpha transcription factor loop.

The feed-forward loop between the transcription factors Ppar-gamma and C/ebp-alpha is critical for lineage commitment during adipocytic differentiation. Ppar-gamma interacts with epigenetic cofactors to activate C/ebp-alpha and the downstream adipocytic gene expression program. Therefore, knowledge of the epigenetic cofactors associated with Ppar-gamma, is central to understanding adipocyte differentiation in normal differentiation and disease. We found that Prmt6 is present with Ppar-gamma on the Ppar-gamma and C/ebp-alpha promoter. It contributes to the repression of C/ebp-alpha expression, in part through its ability to induce H3R2me2a. During adipocyte differentiation, Prmt6 expression is reduced and the methyltransferase leaves the promoters. As a result, the expression of Ppar-gamma and C/ebp-alpha is upregulated and the adipocytic gene expression program is established. Inhibition of Prmt6 by a small molecule enhances adipogenesis, opening up the possibility of epigenetic manipulation of differentiation. Our data provide detailed information on the molecular mechanism controlling the Ppar-gamma-C/ebp-alpha feed-forward loop. Thus, they advance our understanding of adipogenesis in normal and aberrant adipogenesis.

Contributions of the histone arginine methyltransferase PRMT6 to the epigenetic function of RUNX1.

Hematopoietic differentiation is directed by transcription factors such as RUNX1. RUNX1 binds to specific DNA binding sites in regulatory elements of genes and recruits epigenetic cofactors to target loci. In this way histone modification patterns and the chromatin environment are altered, which results in adjusted gene expression. The process of transcription factor binding and cofactor recruitment is dynamic and strongly influenced by specific posttranslational modifications, which are triggered by signaling. In this way cellular signaling is integrated at the epigenetic level by transcription factors. The identification of epigenetic cofactors and the study of their epigenetic influence on transcription is crucial for the understanding of transcription factor function in differentiation and disease. In this article, the recent observation that RUNX1 is associated with the protein arginine methyltransferase 6 will be reviewed. PRMT6 triggers H3R2me2a at RUNX1 target genes; this histone modification negatively influences the positive H3K4me3 mark and this way acts repressive. The RUNX1/PRMT6 association has an impact on bivalent histone marks. Upon differentiation, a RUNX1 corepressor complex with PRMT6 is exchanged with a RUNX1 coactivator complex. Furthermore, the potential cross talk of transcription factors and epigenetic cofactors with histone marks will be discussed.

PRMT6 activates cyclin D1 expression in conjunction with the transcription factor LEF1.

The establishment of cell type specific gene expression by transcription factors and their epigenetic cofactors is central for cell fate decisions. Protein arginine methyltransferase 6 (PRMT6) is an epigenetic regulator of gene expression mainly through methylating arginines at histone H3. This way it influences cellular differentiation and proliferation. PRMT6 lacks DNA-binding capability but is recruited by transcription factors to regulate gene expression. However, currently only a limited number of transcription factors have been identified, which facilitate recruitment of PRMT6 to key cell cycle related target genes. Here, we show that LEF1 contributes to the recruitment of PRMT6 to the central cell cycle regulator CCND1 (Cyclin D1). We identified LEF1 as an interaction partner of PRMT6. Knockdown of LEF1 or PRMT6 reduces CCND1 expression. This is in line with our observation that knockdown of PRMT6 increases the number of cells in G1 phase of the cell cycle and decreases proliferation. These results improve the understanding of PRMT6 activity in cell cycle regulation. We expect that these insights will foster the rational development and usage of specific PRMT6 inhibitors for cancer therapy.

The transcription factor TAL1 and miR-17-92 create a regulatory loop in hematopoiesis.

A network of gene regulatory factors such as transcription factors and microRNAs establish and maintain gene expression patterns during hematopoiesis. In this network, transcription factors regulate each other and are involved in regulatory loops with microRNAs. The microRNA cluster miR-17-92 is located within the MIR17HG gene and encodes six mature microRNAs. It is important for hematopoietic differentiation and plays a central role in malignant disease. However, the transcription factors downstream of miR-17-92 are largely elusive and the transcriptional regulation of miR-17-92 is not fully understood. Here we show that miR-17-92 forms a regulatory loop with the transcription factor TAL1. The miR-17-92 cluster inhibits expression of TAL1 and indirectly leads to decreased stability of the TAL1 transcriptional complex. We found that TAL1 and its heterodimerization partner E47 regulate miR-17-92 transcriptionally. Furthermore, miR-17-92 negatively influences erythroid differentiation, a process that depends on gene activation by the TAL1 complex. Our data give example of how transcription factor activity is fine-tuned during normal hematopoiesis. We postulate that disturbance of the regulatory loop between TAL1 and the miR-17-92 cluster could be an important step in cancer development and progression.