Complex chromosomal rearrangements leading to MECOM overexpression are recurrent in myeloid malignancies with various 3q abnormalities

Abstract

Chromosomal rearrangements involving 3q26 are recurrent findings in myeloid malignancies leading to MECOM overexpression, which has been associated with a very poor prognosis. Other 3q abnormalities have been reported and cryptic MECOM rearrangements have been identified in some cases. By fluorescence in situ hybridization (FISH) analysis, we investigated 97 acute myeloid leukemia/myelodysplastic syndrome patients with various 3q abnormalities to determine the role and the frequency of the involvement of MECOM. We identified MECOM rearrangements in 51 patients, most of them showed 3q26 involvement by chromosome banding analysis (CBA): inv(3)/t(3;3) (n = 26) and other balanced 3q26 translocations (t(3q26)) (n = 15); the remaining cases (n = 10) showed various 3q abnormalities: five with balanced translocations involving 3q21 or 3q25; two with homogenously staining region (hsr) on 3q; and three with other various 3q abnormalities. Complex rearrangements with multiple breakpoints on 3q, masking 3q26 involvement, were identified in cases with 3q21/3q25 translocations. Furthermore, multiple breaks were observed in two cases with t(3q26), suggesting that complex rearrangement may also occur in apparently simple t(3q26). Intrachromosomal gene amplification was another mechanism leading to MECOM overexpression in two cases with hsr on 3q. In the last three cases, FISH analysis revealed 3q26 involvement that was missed by CBA because of metaphases' suboptimal quality. All cases with MECOM rearrangements showed overexpression by real-time quantitative PCR. Finally, MECOM rearrangements can occur in patients with 3q abnormalities even in the absence of specific 3q26 involvement, underlining that their frequency is underestimated. As MECOM rearrangement has been associated with very poor prognosis, its screening should be performed in patients with any 3q abnormalities.

Direct interaction between the PRDM3 and PRDM16 tumor suppressors and the NuRD chromatin remodeling complex

“…Altered MECOM gene expression is commonly associated with initiation and aggressiveness in a variety of hematologic cancers (15). To assess if MECOM expression perturbations are common in other cancer types, we examined MECOM gene expression using RNA-seq data obtained from TCGA from a variety of solid tumor types.…”

“…It is well established that chromosomal aberrations at the PRDM3-encoding gene, MECOM , are found in up to 10% of AML cases with poor survival outcomes (13,14). The expression levels of specific MECOM isoforms suggests that the N-terminal residues of PRDM3 bestow a tumor suppressor function, while the oncogenic shorter EVI1 isoform is overexpressed in myeloid, ovarian, liver and colon tumors, and correlates with poor outcome in AML (1,12,13,15–18). Indeed, this is supported by our comparative analysis of MECOM isoform expression between patient-matched tumor and healthy tissues and identified a previously unreported loss of full-length PRDM3 expression as a common feature of certain solid tumor types, such as renal, lung, prostate and breast carcinomas.…”

“…Additionally, in solid tumors from ovarian and hepatocellular carcinomas, EVI1 overexpression has been shown to drive oncogenesis and progression, while EVI1 in colon cancer was shown to be critical for metastasis (16–18). Aberrant MECOM isoform expression can arise from 3q26 genomic rearrangements imparting an imbalance between EVI1 and PRDM3 isoforms and with it, poor patient survival in AML (15,19). Rearrangements may arise from retroviral insertions between the MDS1 and EVI1 loci, which interrupt normal PRDM3 transcription and lead to EVI1 overexpression (12,20,21).…”

siRNA-dependent Gene Silencing of EVI1 Decreased Cell Proliferation in MKN45 Cells

“…Through the experiment of the study, all patients with MECOM amplification showed MECOM mRNA overexpression with a range of 2.6-54.4, whereas the median MECOM mRNA expression in patients without MECOM rearrangement/amplification was of a range 0.01-0.58 [18]. This indicates that there is a significant correlation between MECOM amplification and the MECOM mRNA overexpression [18]. In addition, amplified MECOM is associated with ovarian cancer [19].…”

“…The previous study identified that the MECOM amplification had been observed at myeloid malignancies and that MECOM amplification associated with MECOM mRNA overexpression [18]. Through the experiment of the study, all patients with MECOM amplification showed MECOM mRNA overexpression with a range of 2.6-54.4, whereas the median MECOM mRNA expression in patients without MECOM rearrangement/amplification was of a range 0.01-0.58 [18]. This indicates that there is a significant correlation between MECOM amplification and the MECOM mRNA overexpression [18].…”