Down-regulation of EVI1 is associated with epigenetic alterations and good prognosis in patients with acute myeloid leukemia

Abstract

The online version of this article has a Supplementary Appendix. BackgroundThe EVI1 gene (3q26) codes for a zinc finger transcription factor with important roles in both mammalian development and leukemogenesis. Over-expression of EVI1 through either 3q26 rearrangements, MLL fusions, or other unknown mechanisms confers a poor prognosis in acute myeloid leukemia. Design and MethodsWe analyzed the prevalence and prognostic impact of EVI1 over-expression in a series of 476 patients with acute myeloid leukemia, and investigated the epigenetic modifications of the EVI1 locus which could be involved in the transcriptional regulation of this gene. ResultsOur data provide further evidence that EVI1 over-expression is a poor prognostic marker in acute myeloid leukemia patients less than 65 years old. Moreover, we found that patients with no basal expression of EVI1 had a better prognosis than patients with expression/over-expression (P=0.036). We also showed that cell lines with over-expression of EVI1 had no DNA methylation in the promoter region of the EVI1 locus, and had marks of active histone modifications: H3 and H4 acetylation, and trimethylation of histone H3 lysine 4. Conversely, cell lines with no expression of EVI1 have DNA hypermethylation and are marked by repressive trimethylation of histone H3 lysine 27 at the EVI1 promoter. ConclusionsOur results identify EVI1 over-expression as a poor prognostic marker in a large, independent cohort of acute myeloid leukemia patients less than 65 years old, and show that the total absence of EVI1 expression has a prognostic impact on the outcome of such patients. Furthermore, we demonstrated for the first time that an aberrant epigenetic pattern involving DNA methylation, H3 and H4 acetylation, and trimethylation of histone H3 lysine 4 and histone H3 lysine 27 might play a role in the transcriptional regulation of EVI1 in acute myeloid leukemia. This study opens new avenues for a better understanding of the regulation of EVI1 expression at a transcriptional level.Key words: AML, EVI1, overexpression, 3q, epigenetics.Citation: Vázquez I, Maicas M, Cervera J, Agirre X, Marin-Béjar O, Marcotegui N, Vicente C, Lahortiga I, Gomez-Benito M, Carranza C, Valencia A, Brunet S, Lumbreras E, Prosper F, Gómez-Casares MT, Hernández-Rivas JM, Calasanz MJ, Sanz MA, Sierra J, and Odero MD. Down-regulation of EVI1 is associated with epigenetic alterations and good prognosis in patients with acute myeloid leukemia. Haematologica 2011;96(10):1448-1456. doi:10.3324/haematol.2011 This is an open-access paper. Down-regulation of EVI1 is associated with epigenetic alterations and good prognosis in patients with acute myeloid leukemia

The oncogeneEVI1enhances transcriptional and biological responses of human myeloid cells toall-transretinoic acid

“…However, as with other members of the TGF-b family, there is evidence to suggest that GDF15 turns from a tumor suppressor to a tumor promoter in the course of carcinogenesis. 64,65 The data presented in this report imply EVI1, a developmental regulator and an oncogene involved in a variety of tumors, [2][3][4][5][13][14][15][16]66,70 and ATRA as novel regulators of GDF15 in both haematopoietic and epithelial cells, and show that GDF15 is required for the reinforcing effect of EVI1 on ATRA induced cell cycle arrest. In addition to providing new information about the regulation and function of this clinically highly relevant cytokine, these results suggest that cooperative interactions between EVI1 and ATRA are not restricted to haematopoietic cells.…”

“…[2][3][4][5] EVI1 overexpression has also been observed in variable proportions of patients with myelodysplastic syndromes (MDS), [6][7][8] chronic myeloid leukemia (CML), [9][10][11] acute lymphoblastic leukemia (ALL), 12 and certain epithelial tumors. [13][14][15][16] An association between elevated EVI1 mRNA levels and poor prognosis is particularly well documented for AML, [2][3][4][5]17,18 but has also been reported for other malignancies. 8,10,13,14 Corroborating its role as an oncogene capable of initiating malignant transformation, in a human gene therapy trial for chronic granulomatous disease clones with activating integrations of the therapeutic vector into the EVI1 locus expanded preferentially, followed by evolution into MDS and, ultimately, AML.…”

EVI1 overexpression is a poor prognostic factor in pediatric patients with mixed lineage leukemia-AF9 rearranged acute myeloid leukemia

“…Hidemasa Matsuo, 1 Mio Kajihara, 1 Daisuke Tomizawa,2 Tomoyuki Watanabe, 3 Akiko Moriya Saito,4 Junichiro Fujimoto, 5 Keizo Horibe, 4 Kumi Kodama, 1 Mayu Tokumasu, 6 Hiroshi Itoh, 1 Hideki Nakayama, 7 Akitoshi Kinoshita, 8 Takashi Taga, 9 Akio Tawa, 10 Tomohiko Taki, 11 Norio Shiba, 12 Kentaro Ohki, 13 Yasuhide Hayashi, 13 Yuka Yamashita, 14 Akira Shimada,…”

“…However, the prognostic value of EVI1 overexpression has been studied mostly in adult AML. [5][6][7][8][9] Only two studies have examined EVI1 overexpression in pediatric AML, but a detailed analysis according to the type of leukemia was not performed because of the small sample size.…”

New Molecular Markers in Acute Myeloid Leukemia

“…When survival curves were analyzed in the AML group with ages ranging from 14 to 60 years, all of them treated with similar chemotherapy schemes, no significant difference was observed. However, a recent collaboration with other groups, showed that EVI1 overexpression is a poor prognostic marker in patients <65 years in an independent large cohort, and showed that the total absence of EVI1 expression has a prognostic impact in the outcome of acute myeloid leukemia patients (Vazquez et al,2011).…”