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.
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Article Synopsis
- The EVI1 gene is linked to a particularly aggressive form of acute myeloid leukemia (AML) characterized by abnormalities on chromosome 3q26.
- Selective and pan-histone deacetylase inhibitors (HDACis) have been identified as effective treatments for this type of leukemia by repressing EVI1 expression.
- The study suggests that the PA2G4 protein plays a key role in EVI1-related leukemia, and targeting PA2G4 could enhance the effects of HDACis, highlighting the potential for combination therapies in patients with 3q26 AML.
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