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inv(3)(q21q26) RPN1::MECOM

Written2012-12Etienne De Braekeleer, Nathalie Douet-Guilbert, Marie-Josée Le Bris, Audrey Basinko, Frédéric Morel, Marc De Braekeleer
Cytogenetics Laboratory, Faculty of Medicine, University of Brest, France

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ICD-Morpho 9861/3 AML with mutated NPM1; AML with mutated CEBPA; Acute myeloid leukaemia, NOS
Atlas_Id 1623
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.
Other namesDouble inversion of the long arm of chromosome 3

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 / cell stem 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 Morphological Double inv(3)(q21q26); additional anomalies including -7.
  Partial karyotype showing the double inv(3)(q21q26) and monosomy 7.
Cytogenetics Molecular Splitting of the probe and rearrangement of the three fluorochromes.
  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 NameMECOM (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 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 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 NameRPN1 (ribophorin I)
Location 3q21.3
Dna / Rna RPN1 has 10 exons. Transcription leads to 8 alternative transcripts, of whose 2 are protein coding.
Protein 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

Hybrid gene
Description RPN1 enhancer juxtaposed to EVI1.

To be noted

Additional cases are needed to delineate the epidemiology of this rare entity:
you are welcome to submit a paper to our new Case Report section.


Rearrangements of chromosome 3 involving bands 3q21 and 3q26 are associated with normal or elevated platelet counts in acute nonlymphocytic leukemia.
Bitter MA, Neilly ME, Le Beau MM, Pearson MG, Rowley JD.
Blood. 1985 Dec;66(6):1362-70.
PMID 4063525
Double Inv(3)(q21q26), a Rare but Recurrent Chromosomal Abnormality in Myeloid Hemopathies.
De Braekeleer E, Douet-Guilbert N, Le Bris MJ, Ianotto JC, Berthou C, Gueganic N, Bovo C, Basinko A, Morel F, De Braekeleer M.
Anticancer Res. 2013 Feb;33(2):639-42.
PMID 23393360
Molecular heterogeneity in AML/MDS patients with 3q21q26 rearrangements.
Lahortiga I, Vazquez I, Agirre X, Larrayoz MJ, Vizmanos JL, Gozzetti A, Calasanz MJ, Odero MD.
Genes Chromosomes Cancer. 2004 Jul;40(3):179-89.
PMID 15138998
Double inversion (3)(q21q26) and monosomy 7 in a case of acute myeloid leukemia.
Lee CL.
Cancer Genet Cytogenet. 1999 May;111(1):99-101.
PMID 10326599
DNA rearrangements proximal to the EVI1 locus associated with the 3q21q26 syndrome.
Levy ER, Parganas E, Morishita K, Fichelson S, James L, Oscier D, Gisselbrecht S, Ihle JN, Buckle VJ.
Blood. 1994 Mar 1;83(5):1348-54.
PMID 8118036
Clinical, 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, Groschel S, Beverloo HB, Kayser S, Valk PJ, van Zelderen-Bhola SL, Jan Ossenkoppele G, Vellenga E, van den Berg-de Ruiter E, Schanz U, Verhoef G, Vandenberghe P, Ferrant A, Kohne CH, Pfreundschuh M, Horst HA, Koller E, von Lilienfeld-Toal M, Bentz M, Ganser A, Schlegelberger B, Jotterand M, Krauter J, Pabst T, Theobald M, Schlenk RF, Delwel R, Dohner K, Lowenberg B, Dohner H.
J Clin Oncol. 2010 Aug 20;28(24):3890-8. doi: 10.1200/JCO.2010.29.2771. Epub 2010 Jul 26.
PMID 20660833
Abnormalities of 3q21 and 3q26 in myeloid malignancy: a United Kingdom Cancer Cytogenetic Group study.
Secker-Walker LM, Mehta A, Bain B.
Br J Haematol. 1995 Oct;91(2):490-501.
PMID 8547101
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).
Suzukawa K, Parganas E, Gajjar A, Abe T, Takahashi S, Tani K, Asano S, Asou H, Kamada N, Yokota J, et al.
Blood. 1994 Oct 15;84(8):2681-8.
PMID 7919381
Cytogenetic and molecular characterization of double inversion 3 associated with a cryptic BCR-ABL1 rearrangement and additional genetic changes.
Toydemir R, Rowe L, Hibbard M, Salama M, Shetty S.
Cancer Genet Cytogenet. 2010 Sep;201(2):81-7. doi: 10.1016/j.cancergencyto.2010.05.014.
PMID 20682391
Apparent duplication of inv(3)(q21q26) in one of five cases with inv (3) in myelodysplastic syndromes and acute leukemia.
Walter TA, Morgan R, Ondreyco S, Sandberg AA.
Am J Hematol. 1990 Mar;33(3):210-4. (REVIEW)
PMID 2405651


This paper should be referenced as such :
De, Braekeleer E ; Douet-Guilbert, N ; Le, Bris MJ ; Basinko, A ; Morel, F ; De, Braekeleer M
Atlas Genet Cytogenet Oncol Haematol. 2013;17(7):491-493.
Free journal version : [ pdf ]   [ DOI ]
On line version :

Translocations implicated (Data extracted from papers in the Atlas)

 inv(3)(q21q26) RPN1/MECOM

External links

Mitelman databaseinv(3)(q21q26)
arrayMap (UZH-SIB Zurich)Topo ( C42) Morph ( 9861/3) -   [auto + random 100 samples .. if exist ]   [tabulated segments]
REVIEW articlesautomatic search in PubMed
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