EVI1 overexpression reprograms hematopoiesis via upregulation of Spi1 transcription

Abstract

Inv(3q26) and t(3:3)(q21;q26) are specific to poor-prognosis myeloid malignancies, and result in marked overexpression of EVI1, a zinc-finger transcription factor and myeloid-specific oncoprotein. Despite extensive study, the mechanism by which EVI1 contributes to myeloid malignancy remains unclear. Here we describe a new mouse model that mimics the transcriptional effects of 3q26 rearrangement. We show that EVI1 overexpression causes global distortion of hematopoiesis, with suppression of erythropoiesis and lymphopoiesis, and marked premalignant expansion of myelopoiesis that eventually results in leukemic transformation. We show that myeloid skewing is dependent on DNA binding by EVI1, which upregulates Spi1, encoding master myeloid regulator PU.1. We show that EVI1 binds to the −14 kb upstream regulatory element (−14kbURE) at Spi1; knockdown of Spi1 dampens the myeloid skewing. Furthermore, deletion of the −14kbURE at Spi1 abrogates the effects of EVI1 on hematopoietic stem cells. These findings support a novel mechanism of leukemogenesis through EVI1 overexpression.

Sleeve Gastrectomy enhances glucose utilization and remodels adipose tissue independent of weight loss

“…Upregulation of transcription factors outlined in Figure 6 are likely underlying these changes. [54] These again include NCOR and SMRT, which both coordinate to modulate the immune response through NF-kB, IRFs and LPS target genes and reduce the pro-inflammatory phenotype of macrophages. [34,35].…”

Multifaceted Role of PRDM Proteins in Human Cancer

“…It is well established that chromosomal rearrangements or proviral insertion at the PRDM3 locus gene, MECOM, are found in up to 10% of acute myeloid leukemia (AML) cases with poor survival outcomes [86,[90][91][92][93][94][95]. The expression levels of particular MECOM isoforms propose that the N-terminal region of PRDM3 confers a tumor suppressor function, while the shorter EVI1 isoform is overexpressed in several malignancies and could have oncogenic properties in both myeloid and solid tumors [96][97][98].…”

“…EVI1 is usually upregulated through the generation of oncogenic fusion proteins as a consequence of rearrangements [101]; alternatively, it can also be upregulated by leukemogenic factors at the transcriptional level [102]. Although increased levels of this protein in several leukemia subtypes are well documented, data from ectopic expression of EVI1 are still weak [94]. Particularly, results from mouse models were quite variable probably due to technical differences and/or to the context-dependent oncogenic function of EVI1, which could be specific to certain hematopoietic cell types [103][104][105][106].…”

Two effects of GATA2 enhancer repositioning by 3q chromosomal rearrangements

“…In contrast to the two preceding model mouse lines, EVI1 ‐expressing mouse models established by Yoshimi et al (in 2011), Yamazaki et al (in 2014), and Ayoub et al (in 2018) all developed myeloid leukemia, in which CD11b + or Gr1 + myeloid leukemia cells are expanded . These mouse models were established by BM transplantation or the transgenic mouse approach (see later in detail).…”

“…In contrast to the two preceding model mouse lines, EVI1-expressing mouse models established by Yoshimi et 4,34,35 These mouse models were established by BM transplantation or the transgenic mouse approach (see later in detail). Nevertheless, it takes a long time (approximately 3-12 months) for these EVI1-overexpressing mouse models to develop leukemia, implying that another hit (DNA mutation) is required for leukemogenesis of the EVI1-expressing cells.…”