inv(3)(q21q26) RPN1/MECOMt(3;3)(q21;q26) RPN1/MECOMins(3;3)(q26;q21q26) RPN1/MECOM

2014-11-01   Thomas Smol 

1.Laboratoire dHematologie-Immunologie-Cytogenetique, Centre Hospitalier de Valenciennes, France
2.Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France

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 stem cell 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 description
EVI1 has 16 exons, and five alternative mRNA 5-ends: EVI1-1A, EVI1-1B, EVI1-1C, EVI1-1D and EVI1-3L.
Protein description
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 description
RPN1 has 10 exons.
Protein description
RPN1 encodes a transmembrane glycoprotein, localized in the rough endoplasmic reticulum.

Result of the Chromosomal Anomaly

Atlas Image
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.

Bibliography

Pubmed IDLast YearTitleAuthors
160143222005Regulation of the expression of the oncogene EVI1 through the use of alternative mRNA 5'-ends.Aytekin M et al
203578262010EVI1 overexpression in distinct subtypes of pediatric acute myeloid leukemia.Balgobind BV et al
173412662007An interphase fluorescence in situ hybridisation assay for the detection of 3q26.2/EVI1 rearrangements in myeloid malignancies.Bobadilla D et al
219657592011Conventional 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 et al
80576671994Correlation of cytogenetic findings with clinical features in 18 patients with inv(3)(q21q26) or t(3;3)(q21;q26).Fonatsch C et al
84353251993Clinical, haematological and cytogenetic features in 24 patients with structural rearrangements of the Q arm of chromosome 3.Grigg AP et al
253810622015Mutational spectrum of myeloid malignancies with inv(3)/t(3;3) reveals a predominant involvement of RAS/RTK signaling pathways.Gröschel S et al
27523701989Acute leukemia with abnormal thrombopoiesis and inversions of chromosome 3.Jenkins RB et al
15818801992Three 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 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
197817752010Immunophenotypic features of acute myeloid leukemia with inv(3)(q21q26.2)/t(3;3)(q21;q26.2).Medeiros BC et al
85471011995Abnormalities of 3q21 and 3q26 in myeloid malignancy: a United Kingdom Cancer Cytogenetic Group study.Secker-Walker LM et al
92094721997Chromosomal abnormality inv(3)(q21q26) associated with multilineage hematopoietic progenitor cells in hematopoietic malignancies.Shi G et al
1045740319993q21 and 3q26 cytogenetic abnormalities in acute myeloblastic leukemia: biological and clinical features.Testoni N et al
247039062014A remote GATA2 hematopoietic enhancer drives leukemogenesis in inv(3)(q21;q26) by activating EVI1 expression.Yamazaki H et al

Summary

Fusion gene

RPN1/MECOM RPN1 (3q21.3) MECOM (3q26.2) M inv(3)(q21q26) t(3;3)(q21;q26)|RPN1/MECOM RPN1 (3q21.3) MECOM (3q26.2) TIC

Note

The three chromosome anomalies are variants of each other, and they share identical features.
Atlas Image
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 u2013 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.

Citation

Thomas Smol

inv(3)(q21q26) RPN1/MECOMt(3;3)(q21;q26) RPN1/MECOMins(3;3)(q26;q21q26) RPN1/MECOM

Atlas Genet Cytogenet Oncol Haematol. 2014-11-01

Online version: http://atlasgeneticsoncology.org/haematological/1006/inv(3)(q21q26)-rpn1-mecomt(3;3)(q21;q26)-rpn1-mecomins(3;3)(q26;q21q26)-rpn1-mecom

Historical Card

1997-10-01 inv(3)(q21q26) RPN1/MECOMt(3;3)(q21;q26) RPN1/MECOMins(3;3)(q26;q21q26) RPN1/MECOM by  Jean-Loup Huret 

Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France