Identification of a breakpoint cluster region 3' of the ribophorin I gene at 3q21 associated with the transcriptional activation of the EVI1 gene in acute myelogenous leukemias with inv(3)(q21q26)

Abstract

Structural alterations occur in the long arm of chromosome 3 in approximately 2% of patients with acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS). The major alterations are inv(3)(q21q26) and t(3:3)(q21;q26) and are often classified as the 3q21q26 syndrome. We previously reported that the EVI1 gene is transcriptionally activated in AMLs with t(3;3)(q21;q26) and inv(3)(q21q26) and that the chromosomal breakpoints at 3q26 in the translocations were 5′ of the EVI1 gene, whereas the breakpoints in the inversion cases were 3′ of the gene. In these studies, four additional cases of AML with inv(3)(q21q26) are shown to express the EVI1 gene and to have breakpoints 3′ of the gene. To characterize the 3q21 breakpoint region, cosmid and phage clones were isolated that cover approximately 100 kb. At 3q21, the breakpoints for both AMLs with t(3;3)(q21;q26) and inv(3)(q21q26) were found to cluster over a region of approximately 50 kb downstream of the Ribophorin I gene. The results indicate a common mechanism for the translocations and inversions and support the hypothesis that the transcriptional activation of the EVI1 gene is mediated by enhancer elements associated with the Ribophorin I gene.

Expression and prognostic significance of different mRNA 5′‐end variants of the oncogene EVI1 in 266 patients with de novo AML: EVI1 and MDS1/EVI1 overexpression both predict short remission duration

“…Chromosome band 3q26.2, which contains the gene coding for the oncogenic transcription factor EVI1, is involved in several types of chromosome rearrangements that are recurrent in dysplastic and neoplastic diseases of myeloid cells (acute myeloid leukemia, AML, chronic myeloid leukemia, CML, and myelodysplastic syndromes, MDS) (Fichelson et al, 1992; Morishita et al, 1992a; Mitani et al, 1994; Nucifora et al, 1994; Suzukawa et al, 1994; Peeters etal., 1997; Stevens‐Kroef etal., 2004). These rearrangements either lead to the formation of EVI1 fusion transcripts (Mitani et al, 1994; Nucifora etal., 1994; Peeters et al, 1997), or to elevated expression of the unaltered EVI1 mRNA (Fichelson et al, 1992; Morishita et al, 1992a; Suzukawa et al, 1994; Vinatzer et al, 2003; Stevens‐Kroef et al, 2004; Poppe et al, 2006). Supportingan oncogenic role of EVI1 , its experimental overexpression inhibited cellular differentiation, promoted proliferation, and interfered with apoptosis (Morishita et al, 1992b; Kreider et al, 1993; Sitailo et al, 1999; Kurokawa etal., 2000; Louz et al, 2000; Chi et al, 2003; Buonamici et al, 2004; Cuenco and Ren, 2004; Buonamici et al, 2005; Kilbey et al, 2005; Liu et al, 2006).…”

Multipoint interphase FISH analysis of chromosome 3 abnormalities in 28 childhood AML patients

“…3q21 is a recurrent; 3q13 is a less common breakpoint for terminal and interstitial deletions in AML (6, 10, 19). A number of 3q21 breakpoints occur within a 30‐kb ‘breakpoint cluster region’ near the enhancer of the RPN1 gene (20, 21); others are located at varying distances (10–60 kb) centromeric to it (22). 3q21 rearrangements exert their oncogenic effect through mechanism acting over some genomic distance.…”

Development of a dual‐color, double fusion FISH assay to detect RPN1/EVI1 gene fusion associated with inv(3), t(3;3), and ins(3;3) in patients with myelodysplasia and acute myeloid leukemia

“…While the EVI1 protein is expressed at low levels in normal hematopoietic cells, inv(3), t(3;3) or ins(3;3) results in the juxtaposition of the promoter for the house‐keeping gene RPN1 placed upstream of the EVI1 gene, resulting in marked over expression of EVI1. Breakpoints in the EVI1 gene region are scattered over several hundred kilobases (kb) with the t(3;3) breakpoints and inv(3) breakpoints located 5′ and 3′ of the EVI1 gene, respectively [10, 14, 15]. Breakpoints in the RPN1 gene span ∼ 100 kb and are located 3′ or centromeric to the RPN1 gene [15–18].…”

“…Breakpoints in the EVI1 gene region are scattered over several hundred kilobases (kb) with the t(3;3) breakpoints and inv(3) breakpoints located 5′ and 3′ of the EVI1 gene, respectively [10, 14, 15]. Breakpoints in the RPN1 gene span ∼ 100 kb and are located 3′ or centromeric to the RPN1 gene [15–18]. The RPN1 promoter‐driven aberrant expression of EVI1 in myeloid cells is thought to be a primary driver in the development of MDS and AML [8, 15, 19, 20].…”

“…Breakpoints in the RPN1 gene span ∼ 100 kb and are located 3′ or centromeric to the RPN1 gene [15–18]. The RPN1 promoter‐driven aberrant expression of EVI1 in myeloid cells is thought to be a primary driver in the development of MDS and AML [8, 15, 19, 20].…”