inv(3)(q21q26) RPN1/MECOM

2012-12-01   Nathalie Douet-Guilbert  , Marie-Josée Le Bris  , Audrey Basinko  , Frédéric Morel  , Marc De Braekeleer  , Etienne De Braekeleer  

1.Cytogenetics Laboratory, Faculty of Medicine, University of Brest, France

Clinics and Pathology

Disease

Myeloid malignancies

Note

This is a rare chromosomal rearrangement, described in only ten patients with myeloid diseases to date (Walter et al., 1990; Levy et al., 1994; Secker-Walker et al., 1995; Lee, 1999; Lahortiga et al., 2004; Toydemir et al., 2010; Lugthart et al., 2010; De Braekeleer et al., 2013).

Phenotype stem cell origin

There were 2 cases of M1 acute myeloid leukemia (AML-M1), 2 cases of AML-M4, 3 cases of AML not otherwise specified, 2 cases of chronic myelogenous leukemia (CML) aberrant translocation, and 1 case of refractory anemia (RA).

Epidemiology

The sex ratio is balanced (5M/5F). Median age, so far, is 62-65 years (range 36-83).

Evolution

Scarce data. One patient had a survival of 24 months (Lahortiga et al., 2004), a patient relapsed 6 months later and, eventually, died (survival: 9 months from diagnosis), and another one received standard induction chemotherapy without remission (survival: 4 months following diagnosis) (De Braekeleer et al., 2013).

Prognosis

Over-expression of EVI1 is a marker of poor prognosis in AML.

Cytogenetics

Atlas Image
Partial karyotype showing the double inv(3)(q21q26) and monosomy 7.

Cytogenetics morphological

Double inv(3)(q21q26); additional anomalies including -7.

Cytogenetics molecular

Splitting of the probe and rearrangement of the three fluorochromes.
Atlas Image
FISH with EVI1 Breakapart Cytocell Aquarius probe showing a normal chromosome 3 and an inverted chromosome 3.

Probes

The EVI1 Breakapart Cytocell Aquarius probe contains three probes: a probe (encompassing D3S3364/D3S1614) labeled in Aqua of 562 kb in size centromeric to the EVI1 gene, a probe (encompassing D3S1282) labeled in Spectrum Green of 181 kb covering EVI1 and its flanking regions and a probe (encompassing D3S3523) labeled in Spectrum Orange of 124 kb telomeric to the EVI1 gene (telomeric of MYNN and covering LRRC34).

Additional anomalies

-7/del(7q) was seen in 4 cases.

Genes Involved and Proteins

Note
The key event in the inv(3)(q21q26) is the overexpression of EVI1 (3q26).
Gene name
MECOM (Ecotropic Viral Integration Site 1 (EVI1) and Myelodysplastic Syndrome 1 (MDS1-EVI1)
Location
3q26.2
Note
EVI1 is a nuclear transcription factor that plays an essential role in the proliferation and maintenance of hematopoietic stem cells and can inhibit myeloid differentiation. Two alternative forms exists, one generated from EVI1, the other MECOM (MDS1 and EVI1 complex locus) through intergenic splicing with MDS1 (myelodysplasia syndrome 1), a gene located 140 kb upstream of EVI1.
Dna rna description
EVI1 has 16 exons, of whose 14 are coding. Transcription can initiate from different alternative exons. Several splice variants of the EVI1 mRNA have been described.
Protein description
The protein encoded by this gene is a transcriptional regulator involved in cell differentiation and proliferation, and apoptosis. The encoded protein can interact with transcriptional coactivators (P/CAF, CBP) and corepressors (CTBP1, HDAC) as well as other transcription factors (GATA1, Smad3).
Gene name
RPN1 (ribophorin I)
Location
3q21.3
Dna rna description
RPN1 has 10 exons. Transcription leads to 8 alternative transcripts, of whose 2 are protein coding.
Protein description
This protein, which is a type I integral membrane protein found only in the rough endoplasmic reticulum, constitutes part of the regulatory subunit of the 26S proteasome. It may mediate binding of ubiquitin-like domains to this proteasome.

Result of the Chromosomal Anomaly

Description

RPN1 enhancer juxtaposed to EVI1.

Highly cited references

Pubmed IDYearTitleCitations
346682652022Comparison of myeloid neoplasms with nonclassic 3q26.2/MECOM versus classic inv(3)/t(3;3) rearrangements reveals diverse clinicopathologic features, genetic profiles, and molecular mechanisms of MECOM activation.0

Article Bibliography

Pubmed IDLast YearTitleAuthors
40635251985Rearrangements of chromosome 3 involving bands 3q21 and 3q26 are associated with normal or elevated platelet counts in acute nonlymphocytic leukemia.Bitter MA et al
233933602013Double Inv(3)(q21q26), a rare but recurrent chromosomal abnormality in myeloid hemopathies.De Braekeleer E et al
151389982004Molecular heterogeneity in AML/MDS patients with 3q21q26 rearrangements.Lahortiga I et al
103265991999Double inversion (3)(q21q26) and monosomy 7 in a case of acute myeloid leukemia.Lee CL et al
81180361994DNA rearrangements proximal to the EVI1 locus associated with the 3q21q26 syndrome.Levy ER et al
206608332010Clinical, molecular, and prognostic significance of WHO type inv(3)(q21q26.2)/t(3;3)(q21;q26.2) and various other 3q abnormalities in acute myeloid leukemia.Lugthart S et al
85471011995Abnormalities of 3q21 and 3q26 in myeloid malignancy: a United Kingdom Cancer Cytogenetic Group study.Secker-Walker LM et al
79193811994Identification 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).Suzukawa K et al
206823912010Cytogenetic and molecular characterization of double inversion 3 associated with a cryptic BCR-ABL1 rearrangement and additional genetic changes.Toydemir R et al
24056511990Apparent duplication of inv(3)(q21q26) in one of five cases with inv (3) in myelodysplastic syndromes and acute leukemia.Walter TA et al

Summary

Note

Inv(3)(q21q26) is recognized as a distinctive entity of acute myeloid leukemia (AML) with recurrent genetic abnormalities of prognostic significance. The molecular consequence is the juxtaposition of the ribophorin I (RPN1) gene (located in band 3q21) with the ecotropic viral integration site 1 (EVI1) gene (located in band 3q26.2), resulting in over-expression of EVI1 (Bitter et al., 1985; Suzukawa et al., 1994). Inv(3)(q21q26) in two copies is rare and was first described by Walter et al. in 1990.

Citation

Nathalie Douet-Guilbert ; Marie-Josée Le Bris ; Audrey Basinko ; Frédéric Morel ; Marc De Braekeleer ; Etienne De Braekeleer

inv(3)(q21q26) RPN1/MECOM

Atlas Genet Cytogenet Oncol Haematol. 2012-12-01

Online version: http://atlasgeneticsoncology.org/haematological/1623/inv(3)(q21q26)-rpn1-mecom