Double inv(3)(q21q26.2) in acute myeloid leukemia is resulted from an acquired copy neutral loss of heterozygosity of chromosome 3q and associated with disease progression.

Jun Gu,Keyur P Patel,Pei Lin,Rajyalakshmi Luthra,Xinyan Lu,Bing Bai,Hagop M Kantarjian,Ronald Abraham,Zhenya Tang,Ching-Hua Liu,Guilin Tang,L Jeffrey Medeiros

doi:10.1186/s13039-015-0171-2

Jun Gu, Keyur P Patel + Show 10 more

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https://doi.org/10.1186/s13039-015-0171-2

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Abstract

BackgroundAcute myeloid leukemia (AML) with inv(3)(q21q26.2)/t(3;3)(q21;q26.2) is a distinct clinicopathologic entity with a poor prognosis. However, double inv(3)(q21q26.2) is extremely rare in AML. We report here 3 cases analyzed by oligonucleotide microarray comparative genomic hybridization (aCGH) and single nucleotide polymorphism (SNP). Clinicopathologic, cytogenetic and molecular findings were correlated with clinical outcome to better understand the entity.ResultsThe study group included one man and two women at 56–74 years of age. The AML arose from myelodysplastic syndrome in one patient and from chronic myelomonocytic leukemia in another patient. Monosomy 7 was found as additional cytogenetic finding in one patient. One patient had a single inv(3) in the initial clone and acquired double inv(3) as part of clonal evolution. EVI1 (MECOM) rearrangement was confirmed using metaphase/interphase fluorescence in situ hybridization (FISH). Microarray (aCGH + SNP) data analysis revealed that the double inv(3) was a result of acquiring copy neutral loss of heterozygosity of chromosome 3q: arr[hg19] 3q13.21q29(10,344,387–197,802,470)x2 hmz, spanning ~ 94.3 Mb in size. Mutational profiling showed a PTPN11 mutation at a low level (~10 %) in one patient and wild type FLT3 and RAS in all patients. No patients achieved cytogenetic remission and all died with an overall survival (OS) of 23, 12 and 5 months, respectively.ConclusionsDouble inv(3) is a result of acquired copy neutral loss of heterozygosity, a somatic repair event occurring as a part of mitotic recombination of the partial chromosome 3q. The double inv(3) in AML patients is highly associated with a rapid disease progression.

Highlights

Acute myeloid leukemia (AML) with inv(3)(q21q26.2)/t(3;3)(q21;q26.2) is a distinct clinicopathologic entity with a poor prognosis
Double inv(3)(q21q26.2) is an extremely rare event with about 10 cases reported in the literatures, primarily in AML patients [6,7,8,9] and very rarely in myelodysplastic syndrome (MDS) [10] or the blast phase in chronic myelogeneous leukemia (CML) [11, 12]
Double inv(3) can be detected by the traditional chromosome analysis and/or by fluorescence in situ hybridization (FISH) targeting the MECOM/EVI1 gene locus, both techniques cannot delineate the potential underlying mechanism leading to this abnormality

Summary

Introduction

Acute myeloid leukemia (AML) with inv(3)(q21q26.2)/t(3;3)(q21;q26.2) is a distinct clinicopathologic entity with a poor prognosis. The 2008 World Health Organization (WHO) classification recognized acute myeloid leukemia (AML) with inv(3)(q21q26.2) or t(3;3)(q21;q26.2) and GATA1-EVI1 (MECOM) rearrangement as a clinicopathologic entity, associated with poor clinical outcomes. This disease accounts for less than 2 % of all cases of AML [1, 2] including de novo and AMLs transformed from myelodysplastic syndrome (MDS) [3]. Double inv(3)(q21q26.2) is an extremely rare event with about 10 cases reported in the literatures, primarily in AML patients [6,7,8,9] and very rarely in MDS [10] or the blast phase in CML [11, 12]. One recent report using single nucleotide polymorphism (SNP) microarrays revealed evidence of an acquired copy neutral loss of heterozygosity (aCN-LOH) or acquired segmental uniparental disomy (aUPD) of only chromosome 3q, instead of the entire chromosome 3, in a CML patient in blast phase [11]

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