| 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 |
 | |
| 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. | |
 | |
| 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. |
| PMID 21965759 |
| 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. |
| PMID 8057667 |
| 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. |
| PMID 25381062 |
| Acute leukemia with abnormal thrombopoiesis and inversions of chromosome 3. |
| 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. |
| Jotterand Bellomo M, Parlier V, Muhlematter D, Grob JP, Beris P. |
| Cancer Genet Cytogenet. 1992 Apr;59(2):138-60. (REVIEW) |
| 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. |
| J Clin Oncol. 2010 Aug 20;28(24):3890-8. doi: 10.1200/JCO.2010.29.2771. Epub 2010 Jul 26. |
| PMID 20660833 |
| 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. |
| Leuk Res. 2010 May;34(5):594-7. doi: 10.1016/j.leukres.2009.08.029. Epub 2009 Sep 24. |
| PMID 19781775 |
| 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 |
| Chromosomal abnormality inv(3)(q21q26) associated with multilineage hematopoietic progenitor cells in hematopoietic malignancies. |
| Shi G, Weh HJ, Duhrsen U, Zeller W, Hossfeld DK. |
| Cancer Genet Cytogenet. 1997 Jul 1;96(1):58-63. |
| PMID 9209472 |
| 3q21 and 3q26 cytogenetic abnormalities in acute myeloblastic leukemia: biological and clinical features. |
| Testoni N, Borsaru G, Martinelli G, Carboni C, Ruggeri D, Ottaviani E, Pelliconi S, Ricci P, Pastano R, Visani G, Zaccaria A, Tura S. |
| Haematologica. 1999 Aug;84(8):690-4. |
| PMID 10457403 |
| A remote GATA2 hematopoietic enhancer drives leukemogenesis in inv(3)(q21;q26) by activating EVI1 expression. |
| Yamazaki H, Suzuki M, Otsuki A, Shimizu R, Bresnick EH, Engel JD, Yamamoto M. |
| Cancer Cell. 2014 Apr 14;25(4):415-27. doi: 10.1016/j.ccr.2014.02.008. Epub 2014 Apr 3. |
| PMID 24703906 |
| 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 |
| © Atlas of Genetics and Cytogenetics in Oncology and Haematology | indexed on : Mon Dec 14 18:24:52 CET 2020 |
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