Inv(3)(q21q26) GATA2::MECOM t(3;3)(q21;q26) GATA2::MECOM ins(3;3)(q26;q21q26) GATA2::MECOM

2022-12-30   Claire Bracquemart , Nasséra Abermil , Hélène Guermouche 

1.Normandie Univ, UNICAEN, CHU de Caen Normandie, Structure Fédérative d'Oncogénétique cyto-Moléculaire (MOCAE), 14000 Caen, France
2.Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine, CRSA, APHP, Hôpital Saint-Antoine, 75012, Paris,


Clinics and Pathology


Inv(3) and t(3;3) have been documented in de novo AML (in all FAB subtypes except M3), therapy related AML (t-AML), MDS, CML, more often in accelerated phase or blast crisis, chronic myelomonocytic leukemia (CMML), and in other myeloproliferative disorders 14-17.

AML with inv(3)(q21q26) or t(3;3)(q21;q26) is part of the new AML with MECOM rearrangement (WHO 2022 classification in the AML subgroup with defining genetic abnormalities 18).

Rare cases of lymphoid malignancies with inv(3) or t(3;3) have been described as well (acute lymphoblastic leukemia, chronic lymphocytic leukemia, among others) (Milteman Database or 19-23). Nevertheless, most cases have not been characterized by FISH analysis. Only one t(3;3)(q21;q26) case is well documented with a EVI1 rearrangement identified by FISH in an acute lymphoblastic leukemia secondary to a myelodysplastic syndrome with 5q deletion 24.


AML : 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.

MDS : inv(3)(21q26)/t(3;3)(q21;q26) occur approximatively in 1% of MDS 25,26. These rearrangement are associated with aggressive disease and high risk of AML transformation.

CML : Chromosome 3 aberrations are described in ~1.5% of CML patients, of which 20-40% are in blast crisis. Among these abnormalities, inv(3) and t(3;3) were detected in 26% of the patients 27,28.

GATA2::MECOM is a rare event in BCR::ABL1 negative myeloproliferative neoplasms and myelodysplastic/myeloproliferative neoplasms.

3q26 rearrangements were also reported in lymphoid malignancies but without evidence of MECOM involvement.


No specific clinical sign.


Patients may present a normal platelet count, however marked thrombocytosis may occur in 7% to 22% of patients 29,30

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) 31. In peripheral blood, morphological abnormalities may be observed : hypogranular neutrophils, pseudo-Pelger anomaly, macrothrombocytes, circulating micromegakaryocytes.


Phenotype stem cell origin: Hematopoietic stem cell with multilineage potential is implicated.

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 32,33.


Patients with inv(3)(q21q26) or t(3;3)(q21;26) present an aggressive course with short overall survival (OS) and poor response to conventional therapy, regardless of the pathology 34. These anomalies are considered to have an adverse prognosis according to the European LeukemiaNet 2022 35. There is no difference in survival between inv(3) and t(3;3).

Table 1 : Pronostic significance of t(3;3)/inv(3) in myeloid malignancies, adapted from Summerer I et al 36

OS is shortened when ACAs are present, especially with additional monosomy 7 or with 2 or more somatic mutations in particular with TP53, NRAS or U2AF1 mutations 36. In CML, 3q26.2 rearrangement remains an independent adverse prognostic factor after adjusting other high-risk ACAs.


Cytogenetics morphological

Inv(3)(q21q26) or t(3;3)(q21;q26) (Conventionnal Cytogenetics and FISH in Figure 1)

Inv(3)(q21q26) or t(3;3)(q21;q26) leads to an inappropriate expression of EVI1 and GATA2 genes, without gene fusion.

Figure 1 : chromosomal aspects on conventional cytogenetics and Fluorescence in situ hybridization for inv(3)(q21q26) GATA2::MECOM and t(3;3)(q21;q26) GATA2::MECOM

Top row : inv(3)(q21q26) G-banding - 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), R-banding - Courtesy Nasséra Abermil, inv(3)(q21q26)x2 R-banding - Courtesy Claire Bracquemart

Second row : t(3;3)(q21;q26) G-banding - Courtesy Diane H. Norback, Eric B. Johnson, Sara Morrison-Delap - Courtesy Christiane Charrin; Adriana Zamecnikova, R-banding - Courtesy Nasséra Abermil

Fluorescence in situ hybridization with the EVI1 (MECOM) Breakapart MetaSystems probe showing MECOM rearrangement as a result of inv(3)(q21q26), t(3;3)(q21;q26) -Courtesy Nasséra Abermil; and inv(3)(q21q26)x2 - Courtesy Claire Bracquemart

Proportion among MECOM anomalies:

inv(3)(q21q26) are the most frequent anomalies (52%), ins(3;3)(q26;q21q26) (9%) are less frequent 1.

Result of chromosome anomaly

Breakpoints of the inv(3) and t(3;3) differ. 3q21 breakpoints cluster in a 130 kb region between GATA2 and RPN1, and share a commonly translocated region of 18kb size before RPN1 for inv(3) and t(3;3) rearrangements that contains a distal GATA2 enhancer (G2DHE). In the 3q26 cytogenetic band, inversion breakpoints span the last intron or downstream of EVI1, whereas translocation breakpoints are located upstream of EVI1 in the MDS1 region (figure 2).

The relocation of the GATA2 enhancer located directly upstream of RPN1 causes EVI1 and GATA2 deregulation. This single enhancer rearrangement generates both EVI1 ectopic activation, by inappropriate transcriptional control, and GATA2 functional haploinsufficiency by removal of that same enhancer 2.

Figure 2 : Schematic representation of GATA2 and MECOM loci. Boxes represent genes.

Top : GATA2, G2DHE (GATA2 distal hematopoietic enhancer), RPN1 are located in 3q21 cytogenetic band; MECOM is located in 3q26 cytogenetic band. Breakpoints in 3q26 band vary between translocations and inversions involving MECOM locus.

Bottom : Inversion(3) is a paracentric inversion of chromosome 3 with two breakpoints on the same chromosome 3 (3q21 and 3q26 upstream MECOM locus); Translocation t(3;3) between the two chromosomes 3, one breakpoint is in 3q21 and one downstream MECOM locus of the homologous chromosome 3.

Diagram is not in scale. Adapted from Thomas Smol diagram and Gröschel S et al. 2; courtesy Claire Bracquemart.

Additional anomalies/variants

In myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), additional chromosomal anomalies (ACAs) are common (68% of cases) 3. The most frequent are monosomy 7 and deletion 7q, the first being more frequent, found in 40-70% of cases 4. Two major deleted regions in 7q35-36 have been identified 5. Deletion 5q occurs in 6-19% of cases 6. These anomalies are usually identified in a complex karyotype in 21% of cases, and monosomal karyotype in 68%.

Inv(3) and t(3;3) can be associated with t(9;22)(q34;q11) in blast phase of chronic myeloid leukemia (CML), often in a complex karyotype 6.

In some cases, both chromosomes 3 can be involved, presenting with a double inv(3)(q21q26) 6 (Figure 1).

Molecular profile

Gröschel and colleagues have shown among 41 inv(3)/t(3;3) cases (32 AML, 4 CML, 5 MDS), that the most common associated mutations were those in genes activating RAS/RTK signaling (98%). Among those mutations, 47% were directly affecting NRAS (27%), KRAS (11%), and also NF1 (9%), PTPN11. Their molecular analysis also showed mutations in a transcription factor (32%), most commonly GATA2 (15%), RUNX1 (12%), in splice factor-encoding genes (29%), such as SF3B1, epigenetic modifier genes (29%), tumor suppressor genes (10%), DNA methylation genes (10%) and cohesion-complex genes (5%). No discrimination difference was found between MDS and AML based on gene expression 7,8.

Result of the Chromosomal Anomaly

Hybrid gene

MECOM = MDS1 and EVI1 complex locus, is a locus composed of two genes : EVI1 (Ecotropic Viral Integration Site 1) and MDS1 (Myelodysplastic Syndrome 1)

Figure 3 : Schematic representation of MECOM locus, from Maicas M et a. 9.

Location 3q26.2

Note Alias EVI1.

Dna rna description MDS1 has 3 exons. EVI1 has 16 exons, and five alternative mRNA 5-ends : EVI1-1A, EVI1-1B, EVI1-1C, EVI1-1D and EVI1-3L. A sixth mRNA 5-end exists and is a combination of MDS1 and EVI1 gene, it starts to the ATG codon of MDS1. Three MECOM protein isofroms have been described : EVI1-145kDa, EVI1-Δ324 and MDS1-EVI1 (9, Figure 3).

Protein description: EVI1 encodes a nuclear zinc finger protein that is a transcriptional regulator involved in cell proliferation, differentiation, and apoptosis. It plays a role in hematopoiesis 10,11 with strong expression in CD34+ hematopoietic stem cells, with decreased expression during differentiation into myeloid lineages 12. The role of Evi1 in hematopoiesis and Evi1 deregulation in leukaemogenesis have been well described, however, the roles of Mds1 and Mds1-Evi1 remain undefined 13.

GATA2 (GATA Biding Protein 2)

Location 3q21.3

Dna rna description GATA2 has 6 exons (NM_032638).

Protein description GATA2 encodes a zing finger transcription factor, member of the GATA family. Multiple transcripts variants exists. It has a key role in hematopoietic development.


Reference NumberPubmed IDLast YearTitleAuthors
1311939892019Data on MECOM rearrangement-driven chromosomal aberrations in myeloid malignancies.Tang Z et al
2247037112014A single oncogenic enhancer rearrangement causes concomitant EVI1 and GATA2 deregulation in leukemia.Gröschel S et al
3219657592011Conventional 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
4337537152021EVI1 dysregulation: impact on biology and therapy of myeloid malignancies.Birdwell C et al
5200842772010Identification of two critically deleted regions within chromosome segment 7q35-q36 in EVI1 deregulated myeloid leukemia cell lines.De Weer A et al
6311095912019Deciphering the complexities of MECOM rearrangement-driven chromosomal aberrations.Tang Z et al
7253810622015Mutational spectrum of myeloid malignancies with inv(3)/t(3;3) reveals a predominant involvement of RAS/RTK signaling pathways.Gröschel S et al
8212830842011The inv(3)(q21q26)/t(3;3)(q21;q26) is frequently accompanied by alterations of the RUNX1, KRAS and NRAS and NF1 genes and mediates adverse prognosis both in MDS and in AML: a study in 39 cases of MDS or AML.Haferlach C et al
9283910502017The MDS and EVI1 complex locus (MECOM) isoforms regulate their own transcription and have different roles in the transformation of hematopoietic stem and progenitor cells.Maicas M et al
10160143222005Regulation of the expression of the oncogene EVI1 through the use of alternative mRNA 5'-ends.Aytekin M et al
11264968312015The role of EVI-1 in normal hematopoiesis and myeloid malignancies (Review).Yuan X et al
12231552562012EVI1 and MDS1/EVI1 expression during primary human hematopoietic progenitor cell differentiation into various myeloid lineages.Steinleitner K et al
13211909932011Evi-1 is a transcriptional target of mixed-lineage leukemia oncoproteins in hematopoietic stem cells.Arai S et al
1484353251993Clinical, haematological and cytogenetic features in 24 patients with structural rearrangements of the Q arm of chromosome 3.Grigg AP et al
1580576671994Correlation of cytogenetic findings with clinical features in 18 patients with inv(3)(q21q26) or t(3;3)(q21;q26).Fonatsch C et al
162928891020183q26/EVI1 rearrangement in myelodysplastic/myeloproliferative neoplasms: An early event associated with a poor prognosis.Hu Z et al
17319900862020Clonal selection in therapy-related myelodysplastic syndromes and acute myeloid leukemia under azacitidine treatment.Calleja A et al
18357328312022The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms.Khoury JD et al
19235218172013T-cell acute lymphoblastic leukemia/lymphoma with inversion(3)(q21q26).Rashidi A et al
20152624322004Secondary Philadelphia chromosome in a patient with acute lymphoblastic leukemia.Chen L et al
2186114551996Discordant clinical presentation and outcome in infant twins sharing a common clonal leukaemia.Campbell M et al
2213779331992Frequent clonal abnormalities of chromosome band 13q14 in B-cell chronic lymphocytic leukemia: multiple clones, subclones, and nonclonal alterations in 82 midwestern patients.Peterson LC et al
2315020241992Chromosome studies in stimulated lymphocytes of 50 patients with B-cell chronic lymphocytic leukemia.Delhomme-Bachy M et al
24230546482012Acquired EVI1 rearrangement involved in the transformation from 5q- syndrome to pre-B lymphocytic leukemia in a Chinese patient.Liu D et al
25217576022011Myelodysplastic syndrome with inv(3)(q21q26.2) or t(3;3)(q21;q26.2) has a high risk for progression to acute myeloid leukemia.Cui W et al
26244632152014Complex or monosomal karyotype and not blast percentage is associated with poor survival in acute myeloid leukemia and myelodysplastic syndrome patients with inv(3)(q21q26.2)/t(3;3)(q21;q26.2): a Bone Marrow Pathology Group study.Rogers HJ et al
27218728262011Frequent EVI1 translocations in myeloid blast crisis CML that evolves through tyrosine kinase inhibitors.Paquette RL et al
28262437782015Clinical and prognostic significance of 3q26.2 and other chromosome 3 abnormalities in CML in the era of tyrosine kinase inhibitors.Wang W et al
2927523701989Acute leukemia with abnormal thrombopoiesis and inversions of chromosome 3.Jenkins RB et al
3015818801992Three 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
311045740319993q21 and 3q26 cytogenetic abnormalities in acute myeloblastic leukemia: biological and clinical features.Testoni N et al
3292094721997Chromosomal abnormality inv(3)(q21q26) associated with multilineage hematopoietic progenitor cells in hematopoietic malignancies.Shi G et al
33197817752010Immunophenotypic features of acute myeloid leukemia with inv(3)(q21q26.2)/t(3;3)(q21;q26.2).Medeiros BC et al
34206608332010Clinical, 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
35357974632022Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN.Döhner H et al
36321895452020Prognosis of MECOM (EVI1)-rearranged MDS and AML patients rather depends on accompanying molecular mutations than on blast count.Summerer I et al


Claire Bracquemart ; Nasséra Abermil ; Hélène Guermouche

Inv(3)(q21q26) GATA2::MECOM t(3;3)(q21;q26) GATA2::MECOM ins(3;3)(q26;q21q26) GATA2::MECOM

Atlas Genet Cytogenet Oncol Haematol. 2022-12-30

Online version: