Transcriptional activation of the miR-17-92 cluster is involved in the growth-promoting effects of MYB in human Ph-positive leukemia cells

Abstract

MicroRNAs, non-coding regulators of gene expression, are likely to function as important downstream effectors of many transcription factors including MYB. Optimal levels of MYB are required for transformation/maintenance of BCR-ABL1-expressing cells. We investigated whether MYB silencing modulates microRNAs expression in Philadelphia-positive leukemia cells and if MYB-regulated microRNAs are important for the MYB addiction of these cells. 35 microRNAs were modulated by MYB silencing in chronic lymphoid and erythro-myeloid blast crisis BV173 and K562 leukemia cells; 15 of these were concordantly modulated in both lines. We focused on the miR-17-92 cluster because of its oncogenic role in tumors and found that: i) it is a direct MYB target; ii) it partially rescued the impaired proliferation and enhanced apoptosis of MYB-silenced BV173 cells. Moreover, we identified FRZB, a Wnt/β-catenin pathway inhibitor, as a novel target of the miR-17-92 cluster. High expression of MYB in blast cells from two Ph-positive leukemia patients correlated positively with the miR-17-92 cluster and inversely with FRZB. This expression pattern was also observed in a microarray dataset of 122 Ph-positive acute lymphoblastic leukemias. In vivo experiments in NOD scid gamma mice injected with BV173 cells confirmed that FRZB functions as a Wnt/β-catenin inhibitor even as they failed to demonstrate that this pathway is important for BV173-dependent leukemogenesis. These studies illustrate the global effects of MYB expression on the microRNAs profile of Ph-positive cells and supports the concept that the MYB addiction of these cells is, in part, caused by modulation of microRNA-regulated pathways affecting cell proliferation and survival.

The Wnt/β-Catenin/LEF1 Pathway Promotes Cell Proliferation at Least in Part Through Direct Upregulation of miR-17-92 Cluster

“…The canonical Wnt/β-catenin pathway is activated when the Wnt ligand binds to the Frizzled (FZD) receptor and its co-receptor from the low-density lipoprotein receptor-related protein 5/6 class (LRP5/6) (MacDonald et al, 2009). Previous studies have demonstrated that the miR-17-92 cluster could regulate Wnt signaling via directly targeting Wnt pathway components, such as FZD4 and LRP6 (Landskroner-Eiger et al, 2015) or the Wnt signaling inhibitors FRZB and HIPK1 (Wu et al, 2013; Spagnuolo et al, 2019). In addition, the miR-17-92 cluster could inhibit Wnt signaling via targeting E2F1.…”

“…To date, a number of other transcription factors have been identified as direct regulators of MIR17HG transcription. Among the identified regulators, c-Myc, N-Myc, STAT3, STAT5, MYCN, MYB, Spi-1, Fli-1, Pim-1, cyclin D1, AML1, ETS1, ETS2, NKX3.1, and E2F family members activate (Fontana et al, 2007; Sylvestre et al, 2007; Yu et al, 2008; De Brouwer et al, 2012; Feuermann et al, 2012; Kayali et al, 2012; Thomas et al, 2013; Kabbout et al, 2014; Yang et al, 2015; Spagnuolo et al, 2019), whereas p53 and C/EBPβ suppress the transcription of MIR17HG (Yan et al, 2009; Yan et al, 2016).…”

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

“…Several transcription factors with a role in differentiation and proliferation control, have been found to transcriptionally activate miR-17-92, such as RUNX1, EGR2, p53, FLI1 and MYC 47,[63][64][65] (also see 66 ). Transcriptional activation of the miR-17-92 cluster by the transcription factor MYB is implicated in the growth-promoting effects of MYB in Ph-positive leukemia cells 67 . This direct activation of miR-17-92 by MYB was also observed in K562 cells.…”

Regulation of MYB by distal enhancer elements in human myeloid leukemia

“…Previous studies indicated that MYB transcription is mainly regulated through a transcriptional attenuation site within the first intron 14 , 15 . miRNAs including miR-150 and miR-17-92 can target MYB mRNA in a stage-specific manner 16 , 17 . PU.1 negatively regulates the c-myb promoter during granulocytic differentiation 18 .…”