t(3;21)(q26;q22) RUNX1/MECOM

2013-08-01   Jean-Loup Huret 

1.Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
2.Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France (JLH); Laboratoire de Biologie, Hopital du Val de Grace, 75230 Paris, France (FD)

Clinics and Pathology

Disease

Chronic myelogenous leukemia in blast crisis (BC-CML), myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).

Note

Cases of t(3;21)(q26;q22) are mostly treatment-related blast crises of CML, and treatment-related MDS/AMLs. However, the t(3;21) may also be found in rare instances of CML prior to the onset of blast crisis (Coyle and Najfeld, 1988).
In a study of cases with 3q21 and/or 3q26 abnormalities (Lugthart et al., 2010), no mutation of FLT3-TKD (tyrosine kinase domain), NPM1, CEBPA, KIT, MLL-PTD (partial tandem duplication), K-RAS were found in the t(3;21)(q26;q22) cases; in the whole 3q26 group (inv(3)/t(3;3) excluded), there were 11% of FLT3-ITD (internal tandem duplication) and 25% of N-RAS mutation.Cases of t(3;21) herein reviewed were selected and pooled together from the large studies (Lafage-Pochitaloff-Huvalé et al., 1989; Rubin et al., 1990; Sacchi et al., 1994; Secker-Walker et al., 1995; Jeandidier et al., 2006; Poppe et al., 2006; Lugthart et al., 2010; Paquette et al., 2011); BC-CML cases and MDS/AML cases were separated into two distinct entities for further studies; each entity was then compared with the equivalent entities from the largest study (Yin et al., 2006), and, in the occurence where there was no discrepancy, all the cases in each entity (BC-CML and MDS/AML) were again pooled together. As a matter of fact, the only discrepancy was the sex ratio in MDS/AML entity: 55% male / 45% female patients in the 29 cases from the "large studies" vs 30% male / 70% female patients in the 10 cases from the "largest study". In the review herein below, we therefore study a sample of 42 cases of BC-CML, and 39 cases of MDS/AML. In some instances, the whole sample of cases of t(3;21) harvested in the Mitelman database was taken into account (146 cases).

Etiology

Rubin et al., 1990 noted that t(3;21) represents 3,6% of therapy related MDS/AMLs (t-MDS/AML); they did not find one case of t(3;21) amongst 1500 de novo MDS/AMLs.
Yin et al., 2006 noted that 15 of their 16 BC-CML patients had previously been treated with hydroxyurea, before blast crisis. The occurrence of the t(3;21) heralded blast transformation. The authors conclude that prior treatment with hydroxyurea or other antimetabolites (fludarabine, 5-fluorouracil) are implicated in t(3;21) malignant blood diseases. Paquette et al., 2011, report that MECOM (also known as EVI1) translocations were seen in 12% of BC-CML before tyrosine kinase inhibitors treatments, a percentage reaching 35-40% with current treatments. The authors note that BCR-ABL1 and MECOM collaborate in leukemogenesis in animal models. Coexistence of BCR-ABL1 and MECOM translocation is sufficient to cause evolution towards BC-CML. The interval between the diagnosis of the initial neoplasm and the occurrence of the t(3;21) was 24 months (median, range 3-154 months) in CML-->BC-CML, and 38 months (median, range 6-144 months) for MDS/AML cases (Yin et al., 2006).
In our meta-analysis, 81% of 33 cases of BC-CML and 87% of 31 cases of MDS/AML can be considered to be secondary to previous treatment.
Results presented herein can be compared with those of a study from an International Workshop on treatment related leukemia: "t(3;21)(q26;q22) in treatment related leukemia".

Epidemiology

Translocation t(3;21) represents 0,14% of AML cases and 3% of 3q abnormalities cases (9 cases out of 6515 AML patients) in Lugthart et al., 2010.
Median age was 58 years (range 21-77) in BC-CML (n=42), and around 65 years (range 13-76, only one child) in MDS/AML (n=39).
From 146 cases extracted from the Mitelman database, sex ratio was 1,44 (59% male and 41% female patients). In the 42 cases of BC-CML herein selected for study, there was 71% male and 29% female patients (p

Cytology

Secker-Walker et al., 1995 noted low platelet counts, dysmyelopoiesis, decreased number of megakaryocytes, and micromegakaryocytes in MDS/AML cases; micromegakaryocytes were also seen in BC-CML cases (Yin et al., 2006).
Atlas Image

Prognosis

Poor survival (see figure above). Median survival is 4 months (range 0-21 months, n=18) in the MDS/AML group, and 9 months (range 1-79+ months, n=30 cases, reports from 1995 to 2011) in the BC-CML group. Median survival was 13 months in the most recent cases of BC-CML (n= 20 cases) (Yin et al., 2006; Paquette et al., 2011).

Genes Involved and Proteins

Gene name
MECOM (Ecotropic Viral Integration Site 1 (EVI1) and Myelodysplastic Syndrome 1 (MDS1-EVI1)
Location
3q26.2
Note
MECOM is also known as EVI1 or PRDM3; MECOM symbol means: "MDS1 and EVI1 complex locus".
Protein description
"EVI1" contains two domains of seven and three zinc finger motifs, respectively, a repression domain between the two sets of zinc fingers, and an acidic domain at its C-term. Sequence specific DNA binding protein. Interacts with transcriptional coactivators, corepressors, and other sequence specific transcription factors. MECOM ("MDS1-EVI1") also contains a PR domain from "MDS1" in N-term (Wieser, 2008).
Gene name
RUNX1 (runt-related transcription factor 1 (acute myeloid leukemia 1; aml1 oncogene))
Location
21q22.12
Note
RUNX1 has also been known as AML1 or CBFA2.
Dna rna description
Transcription is from telomere to centromere.
Protein description
Contains a Runt domain and, in the C-term, a transactivation domain, an inhibition domain, and various regulatory regions; forms heterodimers; widely expressed; nuclear localisation; transcription factor (activator) for various hematopoietic-specific genes.

Result of the Chromosomal Anomaly

Note

Breakpoint after exon 5 or 6 in RUNX1. Breakpoints are variable and dispersed along EVI1, MDS1 and the telomeric region of these two genes (Poppe et al., 2006).

Description

Fusion gene: on the der(3); 5 RUNX1 - 3 MECOM.RUNX1/MECOM: 180 kDa. The translocation protein includes the N-term RUNX1 with the Runt domain and most of the gene MECOM, from the second untranslated exon of EVI1 to C-term, which includes the 2 zinc finger motifs, the repression domain, and the acidic domain, or also including the MDS1 PR domain followed by EVI1 domains as noted above.

Oncogenesis

Inappropriate and ectopic expression of MECOM (either as EVI1 or as MDS1-EVI1) (Poppe et al., 2006; Lugthart et al., 2010); interferes with RUNX1 functions in a dominant negative manner.

Highly cited references

Pubmed IDYearTitleCitations
229500732012Detection of RUNX1-MECOM fusion gene and t(3;21) in a very elderly patient having acute myeloid leukemia with myelodysplasia-related changes.4
326769332020Analytical and Potential Clinical Performance of Oncomine Myeloid Research Assay for Myeloid Neoplasms.2
238068102013Novel real-time polymerase chain reaction assay for simultaneous detection of recurrent fusion genes in acute myeloid leukemia.2
253794092014An unusual case of splenomegaly and increased lactate dehydrogenase heralding acute myeloid leukemia with eosinophilia and RUNX1-MECOM fusion transcripts.1

Bibliography

Pubmed IDLast YearTitleAuthors
31626461988Translocation (3;21) in Philadelphia chromosome-positive chronic myelogenous leukemia prior to the onset of blast crisis.Coyle T et al
166161062006Abnormalities of the long arm of chromosome 21 in 107 patients with hematopoietic disorders: a collaborative retrospective study of the Groupe Français de Cytogénétique Hématologique.Jeandidier E et al
27472891989Translocation (3;21) in Philadelphia positive chronic myeloid leukemia: high resolution chromosomal analysis and immunological study on five new cases.Lafage-Pochitaloff-Huvalé 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
218728262011Frequent EVI1 translocations in myeloid blast crisis CML that evolves through tyrosine kinase inhibitors.Paquette RL et al
163421722006EVI1 is consistently expressed as principal transcript in common and rare recurrent 3q26 rearrangements.Poppe B et al
22652511990t(3;21)(q26;q22): a recurring chromosomal abnormality in therapy-related myelodysplastic syndrome and acute myeloid leukemia.Rubin CM et al
75335261994AML1 fusion transcripts in t(3;21) positive leukemia: evidence of molecular heterogeneity and usage of splicing sites frequently involved in the generation of normal AML1 transcripts.Sacchi N et al
85471011995Abnormalities of 3q21 and 3q26 in myeloid malignancy: a United Kingdom Cancer Cytogenetic Group study.Secker-Walker LM et al
165324392006t(3;21)(q26;q22) in myeloid leukemia: an aggressive syndrome of blast transformation associated with hydroxyurea or antimetabolite therapy.Yin CC et al

Summary

Fusion gene

RUNX1/MECOM RUNX1 (21q22.12) MECOM (3q26.2) M t(3;21)(q26;q22)|RUNX1/MECOM RUNX1 (21q22.12) MECOM (3q26.2) TF LAML
Atlas Image
t(3;21)(q26;q22). Left: G-banding - Top - Courtesy Marian Stevens-Kroef; Middle three: Courtesy Steven Richebourg; Center: R-banding - Top: Courtesy Peter Vandenberghe; Middle three: Courtesy Olivier Theisen; Bottom two: Courtesy Christine Perot; Right: FISH with EVI1 break apart probe Courtesy Olivier Theisen.

Citation

Jean-Loup Huret

t(3;21)(q26;q22) RUNX1/MECOM

Atlas Genet Cytogenet Oncol Haematol. 2013-08-01

Online version: http://atlasgeneticsoncology.org/haematological/1009/t(3;21)(q26;q22)

Historical Card

1997-12-01 t(3;21)(q26;q22) RUNX1/MECOM by  Jean-Loup Huret,François Desangles 

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

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