12 One possibility is that the global effects of fusion gene expression favor a chromatin conformation in which RUNX1-ETO can bind AsPr and modify its chromatin interactions. RUNX1-ETO alters global chromatin conformation and promoter-enhancer interactions. Questions remain regarding precisely how the RUNX1-ETO fusion protein mediates altered chromatin looping and whether this is an immediate consequence of fusion gene expression or requires previous chromatin remodeling or destabilization. Key findings of these studies are: (1) that PU.1 is regulated by competition between a coding and a noncoding promoter for interaction with the enhancer, (2) that an enhancer-driven lncRNA promotes looping with the sense promoter, and (3) that CBF AMLs can co-opt these 2 mechanisms to reduce PU.1 expression. 12 The fact that PU.1 repression by this mechanism is reversible may be an opportunity for therapeutic targeting. Furthermore, RUNX1-ETO–mediated repression of the PU.1 locus seems to require active maintenance, similar to other reports of RUNX1-ETO–induced chromatin remodeling. Thus, in RUNX1-ETO AML, PU.1 expression is actively repressed by a chromosomal structure that is unfavorable to interaction of the URE with the sense promoter and enhances expression of an antisense transcript that is known to repress PU.1. Knockdown of RUNX1-ETO, which also induces a more mature myeloid phenotype, increases LOUP levels, reduces the PU.1 asRNA:mRNA ratio, and promotes interaction between URE and PrPr (see figure, panel D). Furthermore, RUNX1-ETO also binds to the URE and diminishes LOUP expression. In line with this finding, CBF AMLs have increased AsPr accessibility and asRNA expression compared with AMLs with a normal karyotype. Similar to wild-type RUNX1, the CBF fusion proteins RUNX1-ETO and CBFβ-MYH11 are able to transactivate AsPr, which suggests the intriguing possibility that PU.1 perturbation in CBF leukemias might be mediated by AsPr. Given the known roles of PU.1 and RUNX1 in AML, both studies focused on PU.1 regulation in leukemia. However, the mechanisms of spatiotemporal control of PU.1 expression are not completely resolved. As with the PrPr, AsPr interacts with and is regulated by the URE. PU.1 expression can be negatively regulated by a long noncoding RNA (lncRNA) (PU.1 antisense RNA ), which reduces both PU.1 messenger RNA (mRNA) and the protein and is initiated by an antisense promoter (AsPr) located in exon 3 11 (see figure, panel A). 7 A key PU.1 upstream regulatory element (URE) is located upstream of the sense promoter (proximal promoter ), and this can be positively regulated by RUNX1, which binds directly to the URE 4,8-10 (see figure, panel A). 6 Conversely, reexpression of PU.1 can cause AML cells to differentiate. 4,7 Reduced expression, but not complete ablation, in mice leads to AML. Levels of PU.1 increase during myelopoiesis, 6 but expression is reduced in a range of acute myeloid leukemia (AML) cells, particularly those with core binding factor (CBF) fusions. 3,4 PU.1 does not function as an on/off switch instead, graded expression levels determine its precise role in specific cell types, 5 and expression levels must be tightly controlled throughout development. The transcription factor PU.1 is a master hematopoietic regulator involved in hematopoietic stem cell maintenance and myeloid and B lymphoid lineages.
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