Structural rearrangements of chromosome 3 in 57 patients with acute myeloid leukemia: clinical, hematological and cytogenetic features

Charrin, C; Belhabri, Amine; Treille-Ritouet, Danielle; Theuil, G.; Magaud, Jean‐Pierre; Fière, D; Thomas, Xavier

doi:10.1038/sj.thj.6200143

Cited by 41 publications

(19 citation statements)

References 34 publications

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“…26 In two patients with AML with a t(2;3) analyzed in a recent review, 16 the breakpoints could be localized 5 0 to EVI1. Other breakpoint clusters in 3q26 rearrangement were previously identified in a position 3 0 to EVI1 in the inv(3)(q21q26), whereas a fusion between ETV6 or AML1 and MDS1 was documented in the t(3;12)(q26;p13) and (3;21)(q26;q21), respectively.…”

Section: Discussionmentioning

confidence: 99%

Characterization of a recurrent translocation t(2;3)(p15–22;q26) occurring in acute myeloid leukaemia

Trubia

Albano

Cavazzini³

et al. 2005

Leukemia

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Six patients with de novo acute myeloid leukemia (AML) and a t(2;3)(p15-21;q26-27) were identified among approximately 1000 cases enrolled in the GIMEMA trial. The t(2;3) was the sole anomaly in three patients, whereas in three cases monosomy 7, trisomy 15 and 22, and trisomy 14 represented additional aberrations. No cryptic chromosome deletions at 5q, 7q, 12p, and 20q were observed. One patient carried a FLT3 D835 mutation; FLT3 internal tandem duplication (ITD) was not detected in three patients tested. Characterization of the translocation breakpoints using a 3q26 BAC contig specific for the PRDM3 locus showed that the breakpoints were located 5 0 to EVI1 as follows: within myelodysplatic syndrome (MDS) intron 1 (# 3), between MDS1 exons 2 and 3 in three patients (# 1, 2, 4) with a 170 bp cryptic deletion distal to the breakpoint in one (# 2), and in a more centromeric position spanning from intron 2 to the 5 0 region of EVI1 (# 6, 5). A set of 2p16-21 BAC probes showed that the breakpoints on chromosome 2p were located within BCL11A in two separate regions (# 1, 4 and # 2-5), within the thyroid adenoma-associated (THADA) gene (# 6) or distal to the ZFP36L2 locus (# 3). Regulatory elements were present in proximity of these breakpoints. RACE PCR studies revealed a chimeric transcript in 1/6 patient analyzed, but no fusion protein. Quantitative PCR showed a 21-58-fold overexpression of the EVI1 gene in all cases analyzed. The patients showed dysplasia of at least two myeloid cell lineages in all cases; they had a low-to-normal platelet count and displayed an immature CD34 þ CD117 þ immunophenotype. Despite intensive chemotherapy and a median age of 43 years (range 36-59), only two patients attained a short-lived response; one patient is alive with active disease at 12 months, five died at 4-14 months. We arrived at the following conclusions: (a) the t(2;3) is a recurrent translocation having an approximate 0.5% incidence in adult AML; (b) breakpoints involve the 5 0 region of EVI1 at 3q26, and the BCL11A, the THADA gene or other regions at 2p16.1-21; (c) cryptic deletions distal to the 3q26 breakpoint may occur in some cases; (d) the juxtaposition of the 5 0 region of EVI1 with regulatory elements normally located on chromosome 2 brings about EVI1 overexpression; (e) clinical outcome in these cases is severe.

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Section: Discussionmentioning

confidence: 99%

Characterization of a recurrent translocation t(2;3)(p15–22;q26) occurring in acute myeloid leukaemia

Trubia

Albano

Cavazzini³

et al. 2005

Leukemia

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“…Clinically, 3q26.2/EVI1 rearrangements correlate with elevated platelet counts, marked hyperplasia with dysplasia of megakaryocytes, an aggressive clinical course and an unfavourable prognosis with conventional therapy (Morishita et al, 1992;Levy et al, 1994;Suzukawa et al, 1994;Charrin et al, 2002; Barjesteh van Waalwijk can Doorn-Khosrovani et al, 2003;Nucifora et al, 2006;Poppe et al, 2006). The most frequent rearrangements resulting in inappropriate activation of EVI1 are inv(3)(q21q2.2) and t(3;3)(q21;q26.2), with a frequency of 7-10% in MDS/AML of which 3% are associated with therapy-related MDS/AML (Nucifora et al, 2006;Poppe et al, 2006).…”

Section: ; Barjesteh Van Waalwijk Canmentioning

confidence: 99%

“…In these 3q26.2 rearrangements, the enhancer of the constitutively expressed housekeeping gene Ribophorin I is juxtaposed to the coding region of EVI1, with the t(3;3) breakpoints usually mapping 5¢ of EVI1 and the inv(3q) breakpoints usually located 3¢ of EVI1 (Morishita et al, 1992;Suzukawa et al, 1994;Nucifora, 1997;Chakraborty et al, 2003;Weiser et al, 2003;Nucifora et al, 2006;Poppe et al, 2006). Other 3q26.2/EVI1 translocations include t(3;12)(q26.2;p13), t(3;21)(q26.2;q22), t(2;3)(p13;q26), t(3;7)(q26;q22), t(3;13)(q27;q13-14) and t(3;17)(q26;q22) (Mitani et al, 1994;Nucifora, 1997;Charrin et al, 2002;Chakraborty et al, 2003;Weiser et al, 2003;Cameron et al, 2006;Haltrich et al, 2006;Nucifora et al, 2006;Poppe et al, 2006;Trubia et al, 2006).…”

Section: ; Barjesteh Van Waalwijk Canmentioning

confidence: 99%

An interphase fluorescence in situ hybridisation assay for the detection of 3q26.2/EVI1 rearrangements in myeloid malignancies

Bobadilla¹,

Enriquez²,

Álvarez³

et al. 2007

Br J Haematol

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SummaryChromosome rearrangements involving band 3q26.2 are associated with myeloid malignancies, aberrant expression of the human ecotropic virus integration site‐1 (EVI1) gene, an unfavourable prognosis and an aggressive clinical course. The 3q26.2 rearrangements are characteristically heterogeneous and typically difficult to detect in poor quality metaphases. To develop a dual‐colour fluorescence in situ hybridisation (FISH) assay for the detection of 3q26.2/EVI1 aberrations, a series of 10 BAC clones corresponding to the EVI1 gene region were systematically evaluated and narrowed down to two probe sets; one probe set encompassed the EVI1 gene extending centromeric, while the second probe set covered the EVI1 gene and extends telomeric. Both probe sets were evaluated on 35 patient samples with cytogenetically defined 3q26.2 rearrangements collected at various treatment time points, the inv(3)(q21q26.2) Kasumi‐4 cell line, and 10 known negative samples. The two‐probe set strategy identified all samples, despite the vast breakpoint heterogeneity observed. In samples from acute myeloid leukaemia and myelodysplastic syndrome cases, the majority of inversion breakpoints were 3′ to EVI1 whereas 3q26.2 translocation breakpoints frequently mapped 5′ to EVI1. However, two 3q26.2 translocation samples had breakpoints 3′ to EVI1. Most inv(3q) chronic myeloid leukaemia samples showed breakpoints within the EVI1 gene. This study demonstrated that, despite the extensive breakpoint heterogeneity observed with 3q26.2 aberrations, this FISH strategy is effective for the detection of 3q26.2 abnormalities in myeloid malignancies.

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“…6,7 In addition to these well-characterized rearrangements, the EVI1 locus is also involved in rare 3q26 aberrations such © F e r r a t a S t o r t i F o u n d a t i o n as the t(3;17)(q26;q22), 8 the t(2;3)(p21~22;q26) 9,10 and the t(3;6)(q26;q25). 11 For these EVI1 rearrangements, the true recurrent nature and the partner chromosomes involved, have not been analyzed in detail. Therefore, we performed an in depth characterization of the 17q breakpoints in 13 hematologic malignancies with a t(3;17).…”

Section: Introductionmentioning

confidence: 99%

EVI1 overexpression in t(3;17) positive myeloid malignancies results from juxtaposition of EVI1 to the MSI2 locus at 17q22

Weer

Speleman²,

Cauwelier³

et al. 2008

Haematologica

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Chromosomal translocations involving the EVI1 locus are a recurrent finding in myeloid leukemia and are associated with poor prognosis. In this study, we performed a detailed molecular characterization of the recurrent translocation t(3;17)(q26;q22) in 13 hematologic malignancies. The EVI1 gene locus was rearranged in all 13 patients and was associated with EVI1 overexpression. In 9 out of 13 patients, the 17q breakpoints clustered in a 250 kb region on band 17q22 encompassing the MSI2 (musashi homologue 2) gene.Expression analyses failed to demonstrate ectopic MSI2 expression or the presence of an MSI2/EVI1 fusion gene. In conclusion, we show for the first time that the t(3;17) is indeed a recurrent chromosomal aberration in myeloid malignancies. In keeping with findings in other recurrent 3q26 rearrangements, overexpression of the EVI1 gene appears to be the major contributor to leukemogenesis in patients with a t(3;17).

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Structural rearrangements of chromosome 3 in 57 patients with acute myeloid leukemia: clinical, hematological and cytogenetic features

Abstract: These data confirm that 3q rearrangements at q21 or q26 are recurring chromosomal abnormalities in AML. Appearing frequently in combination with monosomy 7 and an abnormal megakaryopoiesis, patients with these abnormalities have a particularly poor prognosis.

Cited by 41 publications

References 34 publications

Characterization of a recurrent translocation t(2;3)(p15–22;q26) occurring in acute myeloid leukaemia

Characterization of a recurrent translocation t(2;3)(p15–22;q26) occurring in acute myeloid leukaemia

An interphase fluorescence in situ hybridisation assay for the detection of 3q26.2/EVI1 rearrangements in myeloid malignancies

EVI1 overexpression in t(3;17) positive myeloid malignancies results from juxtaposition of EVI1 to the MSI2 locus at 17q22

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