Amplification and translocation of 3q26 with overexpression of EVI1 in Fanconi anemia‐derived childhood acute myeloid leukemia with biallelic FANCD1/BRCA2 disruption

Abstract

Fanconi anemia (FA) is an inherited disease with congenital abnormalities and an extreme risk of acute myeloid leukemia (AML). Genetic events occurring during malignant transformation in FA and the biology of FA-associated AML are poorly understood, but are often preceded by the development of chromosomal aberrations involving 3q26-29 in bone marrow of FA patients. We report here the molecular cytogenetic characterization of FA-derived AML cell lines SB1685CB and SB1690CB by conventional and array comparative genomic hybridization, fluorescence in situ hybridization, and SKY. We identified gains of a 3.7 MB chromosomal region on 3q26.2-26.31, which preceded transformation to overt leukemia. This region harbors the oncogenic transcription factor EVI1. A third FA-derived cell line, FA-AML1, carried a translocation with ectopic localization of 3q26 including EVI1. Rearrangements of 3q, which are rare in childhood AML, commonly result in overexpression of EVI1, which determines specific gene expression patterns and confers poor prognosis. We detected overexpression of EVI1 in all three FA-derived AML. Our results suggest a link between the FA defect, chromosomal aberrations involving 3q and overexpression of EVI1. We hypothesize that constitutional or acquired FA defects might be a common factor for the development of 3q abnormalities in AML. In addition, cryptic imbalances as detected here might account for overexpression of EVI1 in AML without overt 3q26 rearrangements.

Myelodysplasia and leukemia of Fanconi anemia are associated with a specific pattern of genomic abnormalities that includes cryptic RUNX1/AML1 lesions

“…by guest www.bloodjournal.org From AML cell lines derived from an FA patient of the particular D1/BRCA2 downstream group. 42 Here, break-apart FISH found frequent EVI1 duplication, as expected from the CGH/SNP array data, but no direct involvement in a fusion gene resulting from a translocation. Therefore, the potential role of EVI1 in the MDS/ AMLs with 3qϩ in typical FA-core patients remains elusive.…”

EVI1 carboxy-terminal phosphorylation is ATM-mediated and sustains transcriptional modulation and self-renewal via enhanced CtBP1 association

“…The FA-derived AML cell line SB1690CB, which expresses high levels of EVI1, and the EVI1 negative AML cell line OCI-AML5 were maintained as described previously (10). HEK293T cells and Rat1 fibroblasts were used as previously described (28).…”

“…In acute myeloid leukemia (AML) high EVI1 expression is associated with poor response to cytotoxic treatment and adverse outcome (6,7). EVI1 overexpression has been linked to leukemic transformation in children undergoing gene therapy (8), and individuals affected by Fanconi Anaemia (FA), which is an inherited DNA damage response defect with cancer predisposition (9,10). High EVI1 expression conferring resistance to cytotoxic treatment and poor prognosis is also seen in other malignancies (11–14).…”

Aberrant DNA hypermethylation signature in acute myeloid leukemia directed by EVI1

“…To determine whether the presence of putative EVI1-binding sites indicated that these were EVI1 target genes, we first performed HELP analysis on the human AML SB1690CB cell line, carrying a chromosomal 3q26 aberration and overexpressing EVI1 23 . A highly significant concordance of hypermethylated genes (89%) was found between the SB1690CB cell line and the hypermethylated genes identified in the EVI1 AML patient samples (211/238 genes; supplemental Table 5).…”