Written | 2014-11 | Thomas Smol |
Laboratoire d'Hematologie-Immunologie-Cytogenetique, Centre Hospitalier de Valenciennes, France |
This article is an update of : |
1997-10 | Jean-Loup Huret | |
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France |
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 names | RPN1/EVI1 |
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inv(3)(q21q26) RPN1/MECOM and t(3;3)q21;q26) RPN1/MECOM Top row: 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 (right), Middle and bottom rows: t(3;3)q21;q26) G-banding second row - 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; Third row – Courtesy Adriana Zamecnikova Fluorescence in situ hybridization with the Kreatech MECOM t(3;3); inv(3) (3q26) probe (Leica Biosystems, US) showing MECOM rearrangement as a result of t(3;3)(q2;q26) - Courtesy Adriana Zamecnikova. | |
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 (Ecotropic Viral Integration Site 1 (EVI1) and Myelodysplastic Syndrome 1 (MDS1-EVI1) |
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 (ribophorin I) |
Location | 3q21.3 |
Dna / Rna | RPN1 has 10 exons. |
Protein | RPN1 encodes a transmembrane glycoprotein, localized in the rough endoplasmic reticulum. |
Result of the chromosomal anomaly |
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. | |
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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. |
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Citation |
This paper should be referenced as such : |
Etienne De Braekeleer, Nathalie Douet-Guilbert, Marie-Jos Le Bris, Audrey Basinko, Frdéric Morel |
inv(3)(q21q26) RPN1/MECOM |
Atlas Genet Cytogenet Oncol Haematol. 2015;19(9):190-193. |
Free journal version : [ pdf ] [ DOI ] |
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 |
REVIEW articles | automatic search in PubMed |
Last year articles | automatic search in PubMed |
All articles | automatic search in PubMed |
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