EVI1 is critical for the pathogenesis of a subset of MLL-AF9-rearranged AMLs
ABSTRACT The proto-oncogene EVI1 (ecotropic viral integration site-1), located on chromosome band 3q26, is aberrantly expressed in human acute myeloid leukemia (AML) with 3q26 rearrangements. In the current study, we showed, in a large AML cohort carrying 11q23 translocations, that ∼ 43% of all mixed lineage leukemia (MLL)-rearranged leukemias are EVI1(pos). High EVI1 expression occurs in AMLs expressing the MLL-AF6, -AF9, -AF10, -ENL, or -ELL fusion genes. In addition, we present evidence that EVI1(pos) MLL-rearranged AMLs differ molecularly, morphologically, and immunophenotypically from EVI1(neg) MLL-rearranged leukemias. In mouse bone marrow cells transduced with MLL-AF9, we show that MLL-AF9 fusion protein maintains Evi1 expression on transformation of Evi1(pos) HSCs. MLL-AF9 does not activate Evi1 expression in MLL-AF9-transformed granulocyte macrophage progenitors (GMPs) that were initially Evi1(neg). Moreover, shRNA-mediated knockdown of Evi1 in an Evi1(pos) MLL-AF9 mouse model inhibits leukemia growth both in vitro and in vivo, suggesting that Evi1 provides a growth-promoting signal. Using the Evi1(pos) MLL-AF9 mouse leukemia model, we demonstrate increased sensitivity to chemotherapeutic agents on reduction of Evi1 expression. We conclude that EVI1 is a critical player in tumor growth in a subset of MLL-rearranged AMLs.
Haematologica 07/2014; DOI:10.3324/haematol.2014.107128 · 5.87 Impact Factor
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ABSTRACT: Chromosomal rearrangements without gene fusions have been implicated in leukemogenesis by causing deregulation of proto-oncogenes via relocation of cryptic regulatory DNA elements. AML with inv(3)/t(3;3) is associated with aberrant expression of the stem-cell regulator EVI1. Applying functional genomics and genome-engineering, we demonstrate that both 3q rearrangements reposition a distal GATA2 enhancer to ectopically activate EVI1 and simultaneously confer GATA2 functional haploinsufficiency, previously identified as the cause of sporadic familial AML/MDS and MonoMac/Emberger syndromes. Genomic excision of the ectopic enhancer restored EVI1 silencing and led to growth inhibition and differentiation of AML cells, which could be replicated by pharmacologic BET inhibition. Our data show that structural rearrangements involving the chromosomal repositioning of a single enhancer can cause deregulation of two unrelated distal genes, with cancer as the outcome.Cell 04/2014; DOI:10.1016/j.cell.2014.02.019 · 33.12 Impact Factor
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ABSTRACT: Abstract Ecotropic viral integration site-1 (EVI1) proto-oncogene expression in patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) requires further investigation. Here, EVI1 expression levels were measured in 216 Chinese patients with AML and 67 with ALL via quantitative real-time PCR. We found that EVI1 expressed at a high level (H-EVI1) was present in 11.1% AML patients versus 20.9% ALL. Low levels of EVI1 expression occurred in 23.1% AML versus 43.3% ALL. This suggested that alteration of EVI1 expression were more profound in ALL than AML. H-EVI1 was significantly enriched in 30 ∼ 60-year-old patients. FAB-M3 subtype was significantly correlated with H-EVI1. Interestingly, we found that EVI1 expression was negatively associated with Ph+ and MLL-rearrangements in AML. However, Ph+, but not MLL-rearrangements, was inversely correlated with EVI1 expression in B-ALL. These results for the first time suggest a mutual exclusive relationship between EVI1 expression and Ph+ karyotype.Leukemia & lymphoma 05/2014; DOI:10.3109/10428194.2014.924118 · 2.61 Impact Factor