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.
Highlights
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 myeloidspecific oncoprotein
While Yamazaki et al.[14] previously published an EVI1 transgenic model that genetically mimics the 3q26 human leukemias and underlined the significance of GATA2 enhancer, we report the development of the first Evi1-inducible system that allowed us to uncover a mechanism behind EVI1-associated leukemogenesis
These findings support a model wherein EVI1 acts via PU.[1] to push hematopoietic hematopoietic stem/ progenitor cells (HSPCs) towards the myeloid lineage, with concomitant suppression of erythropoiesis and lymphopoiesis; this myeloid expansion, eventually progresses to acute myeloid leukemia (AML)
Summary
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 myeloidspecific oncoprotein. Chromosomal rearrangements at 3q26 are associated with poor-prognosis acute myeloid leukemia (AML)[1], myelodysplastic syndromes (MDS)[2], and myeloproliferative neoplasms (MPN)[3], and cause activation of MECOM, a gene that encodes multiple zinc-finger (ZF) transcription factor isoforms, including three isoforms of EVI1. While Yamazaki et al.[14] previously published an EVI1 transgenic model that genetically mimics the 3q26 human leukemias and underlined the significance of GATA2 enhancer, we report the development of the first Evi1-inducible system that allowed us to uncover a mechanism behind EVI1-associated leukemogenesis Using this system, Evi[1] induction by doxycycline (DOX) causes a massive perturbation of hematopoietic homeostasis, expanding HSCs, suppressing erythropoiesis and lymphopoiesis, and creating a myeloid-skewed phenotype. These findings support a model wherein EVI1 acts via PU.[1] to push hematopoietic HSPCs towards the myeloid lineage, with concomitant suppression of erythropoiesis and lymphopoiesis; this myeloid expansion, eventually progresses to AML
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