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inv(3)(q21q26) RPN1/MECOM

t(3;3)(q21;q26) RPN1/MECOM

ins(3;3)(q26;q21q26) RPN1/MECOM

Written1997-10Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
Updated2014-11Thomas Smol
Laboratoire d'Hematologie-Immunologie-Cytogenetique, Centre Hospitalier de Valenciennes, France

(Note : for Links provided by Atlas : click)

Identity

ICD-Topo C420,C421,C424 BLOOD, BONE MARROW, & HEMATOPOIETIC SYS
ICD-Morpho 9861/3 AML with mutated NPM1; AML with mutated CEBPA; Acute myeloid leukaemia, NOS
ICD-Morpho 9869/3
ICD-Morpho 9920/3 Therapy-related myeloid neoplasms
ICD-Morpho 9975/3 Chronic myelogenous leukaemia, BCR-ABL1 positive; Myeloproliferative neoplasm, unclassifiable; Myelodysplastic/myeloproliferative neoplasm, unclassifiable
ICD-Morpho 9989/3 Myelodysplastic syndrome, unclassifiable
Atlas_Id 1006
Note The three chromosome anomalies are variants of each other, and they share identical features.
Other namesRPN1/EVI1
 
  inv(3)(q21q26) G-banding (top) - Courtesy Diane H. Norback, Eric B. Johnson, Sara Morrison-Delap Cytogenetics at the Waisman Center (left and middle) and Jean-Luc Lai and Alain Vanderhaegen, bottom: t(3;3)q21;q26) (bottom) G-banding (left) - Courtesy Diane H. Norback, Eric B. Johnson, Sara Morrison-Delap (left and center left), Jean-Luc Lai and Alain Vanderhaegen (middle) , and R-banding (middle right and right) - Courtesy Christiane Charrin.

Clinics and Pathology

Disease inv(3) and t(3;3) have been documented in de novo AML (in all FAB subtypes except M3), t-AML, s-AML, myelodysplastic syndrome (MDS), chronic myelogenous leukaemia (CML), more often in accelerated phase or blast crisis, and in other myeloproliferative disorders. AML with inv(3)(q21q26) or t(3;3)(q21;q26) are part of the new WHO 2008 classification in the AML subgroup with recurrent genetic abnormalities.
Phenotype / cell stem origin Hematopoietic stem cell with multilineage potential is implicated.
Epidemiology inv(3)(q21q26) and t(3;3)(q21;q26) are the most common 3q abnormalities in AML (32%). The frequency of these rearrangements is estimated to range between 1.4% and 1.6% of AML in adults with no difference between sexes. These rearrangements are slightly more common in patients aged 60 years or younger, and extremely rare in pediatric AML.
Clinics Patients may present a normal platelet count, however marked thrombocytosis may occur in 7% to 22% of patients.
Cytology Blasts express CD13, CD33, CD117, HLA-DR, CD56, CD34 and CD38; CD7 is aberrantly expressed in some cases, whereas the other lymphoid markers are uncommon; blasts may also express megakaryocytic markers such as CD41 or CD61.
Blasts present morphologic and cytochemical features of any AML subtypes other than M3. Multilineage dysplasia is frequently associated with dysmegakaryopoiesis (characterized by small monolobate or bilobate megakaryocytes that can be increased in number). In peripheral blood, morphological abnormalities may be observed: hypogranular neutrophil, pseudo-Pelger anomaly, macrothrombocytes, circulating micromegakaryocytes.
Prognosis Patients with inv(3)(q21q26) or t(3;3)(q21;26) present an aggressive course with short OS and poor response to conventional therapy (CR is estimated at 31%). Studies describe an unfavourable 5-year survival rate (OS: 5.7%) with a median survival of 10.3 months. OS is shorter, if additional monosomy 7 is present. There is no difference in survival between inv(3) and t(3;3).

Cytogenetics

Note inv(3)(q21q26) are the most frequent abnormalities, ins(3;3)(q26;q21q26) are less frequent.
Additional anomalies In AML, the most frequent additional anomaly is monosomy 7 (66% of cases), deletion 7q may occur in 3%, deletion 5q in 6%; complex karyotype is observed in 21% of cases, and monosomal karyotype in 68%. In CML, inv(3) or t(3;3) can be an additional anomaly to t(9;22)(q34;q11), but t(9;22) has also been found additional to inv(3).

Genes involved and Proteins

Gene Name MECOM
Location 3q26.2
Note Alias EVI1.
Dna / Rna EVI1 has 16 exons, and five alternative mRNA 5'-ends: EVI1-1A, EVI1-1B, EVI1-1C, EVI1-1D and EVI1-3L.
Protein EVI1 encodes a nuclear zinc finger protein that is a transcriptional regulator involved in cell proliferation, differentiation, and apopotosis.
Gene Name RPN1
Location 3q21
Dna / Rna RPN1 has 10 exons.
Protein RPN1 encodes a transmembrane glycoprotein, localized in the rough endoplasmic reticulum.

Result of the chromosomal anomaly

Hybrid gene
  Boxes represent genes. Breakpoints in 3q26.2 locus are distributed on each side of EVI gene: 5' in t(3;3) and 3' in inv(3). GATA2 = GATA Binding Protein 2; G2DHE = GATA2 distal hematopoietic enhancer. Diagram is not to scale. Courtesy Thomas Smol.
 
Description inv(3)(q21q26) or t(3;3)(q21q26) lead to a juxtaposition of the region surrounding the RPN1 gene in 3q21 with the EVI1 gene in 3q26. Breakpoints occur about 900 kb located 5' and 3' to the EVI1 gene with the t(3;3) and the inv(3) respectively. Breakpoints in the RPN1 gene area span over 235 kb and are either located 3' or centromeric to the RPN1 gene. Recently, studies have described a role for G2DHE, GATA2 distal hematopoietic enhancer, that is located 160 kb 3' to the RPN1 gene on 3q21. In 3q21q26 rearrangements, G2DHE is juxtaposed to EVI1 and is thought to induce EVI1 gene transcription instead of GATA2 and thus promote leukemogenesis.
  

To be noted

AML with inv(3) or t(3;3) are associated with NRAS mutations (28%), FLT3-ITD mutations (less than 20%), and rare NPM1 mutations. EVI1 overexpression has been described without 3q21q26 rearrangement and conversely, there are extremely rare cases of 3q21q26 rearrangement without EVI1 overexpression. Recently, Groschel et al. have observed that 98% of myeloid malignancies with inv(3) and t(3;3) present mutations in gene activating RAS/RTK signalling pathways.

Bibliography

Regulation of the expression of the oncogene EVI1 through the use of alternative mRNA 5'-ends.
Aytekin M, Vinatzer U, Musteanu M, Raynaud S, Wieser R.
Gene. 2005 Aug 15;356:160-8.
PMID 16014322
 
EVI1 overexpression in distinct subtypes of pediatric acute myeloid leukemia.
Balgobind BV, Lugthart S, Hollink IH, Arentsen-Peters ST, van Wering ER, de Graaf SS, Reinhardt D, Creutzig U, Kaspers GJ, de Bont ES, Stary J, Trka J, Zimmermann M, Beverloo HB, Pieters R, Delwel R, Zwaan CM, van den Heuvel-Eibrink MM.
Leukemia. 2010 May;24(5):942-9. doi: 10.1038/leu.2010.47. Epub 2010 Apr 1.
PMID 20357826
 
An interphase fluorescence in situ hybridisation assay for the detection of 3q26.2/EVI1 rearrangements in myeloid malignancies.
Bobadilla D, Enriquez EL, Alvarez G, Gaytan P, Smith D, Slovak ML.
Br J Haematol. 2007 Mar;136(6):806-13.
PMID 17341266
 
Conventional cytogenetics and breakpoint distribution by fluorescent in situ hybridization in patients with malignant hemopathies associated with inv(3)(q21;q26) and t(3;3)(q21;q26).
De Braekeleer E, Douet-Guilbert N, Basinko A, Bovo C, Gueganic N, Le Bris MJ, Morel F, De Braekeleer M.
Anticancer Res. 2011 Oct;31(10):3441-8.
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Correlation of cytogenetic findings with clinical features in 18 patients with inv(3)(q21q26) or t(3;3)(q21;q26).
Fonatsch C, Gudat H, Lengfelder E, Wandt H, Silling-Engelhardt G, Ludwig WD, Thiel E, Freund M, Bodenstein H, Schwieder G, et al.
Leukemia. 1994 Aug;8(8):1318-26.
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Clinical, haematological and cytogenetic features in 24 patients with structural rearrangements of the Q arm of chromosome 3.
Grigg AP, Gascoyne RD, Phillips GL, Horsman DE.
Br J Haematol. 1993 Jan;83(1):158-65.
PMID 8435325
 
Mutational spectrum of myeloid malignancies with inv(3)/t(3;3) reveals a predominant involvement of RAS/RTK signaling pathways.
Groschel S, Sanders MA, Hoogenboezem R, Zeilemaker A, Havermans M, Erpelinck C, Bindels EM, Beverloo HB, Dohner H, Lowenberg B, Dohner K, Delwel R, Valk PJ.
Blood. 2015 Jan 1;125(1):133-9. doi: 10.1182/blood-2014-07-591461. Epub 2014 Nov 7.
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Jenkins RB, Tefferi A, Solberg LA Jr, Dewald GW.
Cancer Genet Cytogenet. 1989 Jun;39(2):167-79.
PMID 2752370
 
Three new cases of chromosome 3 rearrangement in bands q21 and q26 with abnormal thrombopoiesis bring further evidence to the existence of a 3q21q26 syndrome.
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PMID 1581880
 
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.
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Immunophenotypic features of acute myeloid leukemia with inv(3)(q21q26.2)/t(3;3)(q21;q26.2).
Medeiros BC, Kohrt HE, Arber DA, Bangs CD, Cherry AM, Majeti R, Kogel KE, Azar CA, Patel S, Alizadeh AA.
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Chromosomal abnormality inv(3)(q21q26) associated with multilineage hematopoietic progenitor cells in hematopoietic malignancies.
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A remote GATA2 hematopoietic enhancer drives leukemogenesis in inv(3)(q21;q26) by activating EVI1 expression.
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Citation

This paper should be referenced as such :
Smol T
inv(3)(q21q26) RPN1/MECOM; t(3;3)(q21;q26) RPN1/MECOM; ins(3;3)(q26;q21q26) RPN1/MECOM;
Atlas Genet Cytogenet Oncol Haematol. in press
On line version : http://AtlasGeneticsOncology.org/Anomalies/inv3ID1006.html
History of this paper:
Huret, JL. inv(3)(q21q26). Atlas Genet Cytogenet Oncol Haematol. 1997;1(2):72-73.
http://documents.irevues.inist.fr/bitstream/handle/2042/32059/10-1997-inv3ID1006.pdf


Other genes implicated (Data extracted from papers in the Atlas) [ 4 ]

Genes MECOM MECOM GATA2 PRDM16

Translocations implicated (Data extracted from papers in the Atlas)

 inv(3)(q21q26) RPN1/MECOM
 t(3;3)(q21;q26) RPN1/MECOM
 ins(3;3)(q26;q21q26) RPN1/MECOM

External links

RPN1 (3q21.3) MECOM (3q26.2)

RPN1 (3q21.3) MECOM (3q26.2)

Mitelman databaseinv(3)(q21q26) [Case List]    inv(3)(q21q26) [Association List] Mitelman database (CGAP - NCBI)
Mitelman databaset(3;3)(q21;q26) [Case List]    t(3;3)(q21;q26) [Association List] Mitelman database (CGAP - NCBI)
Mitelman databaseins(3;3)(q26;q21q26) [Case List]    ins(3;3)(q26;q21q26) [Association List] Mitelman database (CGAP - NCBI)
arrayMapTopo ( C42) Morph ( 9861/3) - arrayMap (UZH-SIB Zurich)  [auto + random 100 samples .. if exist ]   [tabulated segments]
arrayMapTopo ( C42) Morph ( 9869/3) - arrayMap (UZH-SIB Zurich)  [auto + random 100 samples .. if exist ]   [tabulated segments]
arrayMapTopo ( C42) Morph ( 9920/3) - arrayMap (UZH-SIB Zurich)  [auto + random 100 samples .. if exist ]   [tabulated segments]
arrayMapTopo ( C42) Morph ( 9975/3) - arrayMap (UZH-SIB Zurich)  [auto + random 100 samples .. if exist ]   [tabulated segments]
arrayMapTopo ( C42) Morph ( 9989/3) - arrayMap (UZH-SIB Zurich)  [auto + random 100 samples .. if exist ]   [tabulated segments]
 
Mitelman databaseRPN1/MECOM [MCList]  RPN1 (3q21.3) MECOM (3q26.2)
TICdbRPN1/MECOM  RPN1 (3q21.3) MECOM (3q26.2)
 
Disease databaseinv(3)(q21q26) RPN1/MECOM
REVIEW articlesautomatic search in PubMed
Last year articlesautomatic search in PubMed
All articlesautomatic search in PubMed


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indexed on : Tue Mar 14 13:54:00 CET 2017


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