title: Three novel cytogenetically cryptic EVI1 rearrangements associated with increased EVI1 expression and poor prognosis identified in 27 acute myeloid leukemia cases.
abstract: In acute myeloid leukemia (AML), increased ecotropic virus integration site 1 protein homolog (EVI1) gene expression is prognostically unfavorable. Subsets of cases show 3q26 rearrangements, such as inv(3)(q21q26)/t(3;3)(q21;q26), frequently accompanied by chromosome 7 abnormalities. We investigated whether cytogenetically cryptic EVI1 rearrangements may cause EVI1 overexpression in myeloid malignancies without 3q26 abnormalities and investigated 983 patients with AML (n = 606) or myelodysplastic syndromes (MDS; n = 377) with normal karyotype (CN-AML/CN-MDS, n = 594) or chromosome 7 abnormalities (n = 389) for EVI1 rearrangements using interphase FISH. We identified cytogenetically cryptic EVI1 rearrangements in 27 patients (19 AML, 8 MDS): inv(3)(p24q26) [n = 10]; t(3;21)(q26;q11) [n = 9]; and der(7)t(3;7)(q26;q21) [n = 8]. Elevated EVI1 expression was detected in nearly all cases with cryptic EVI1 rearrangements: Median %EVI1/ABL1 was 92.8 (range: 29.8-146.1) in inv(3)(p24q26), 104.9 (41.4-176.3) in t(3;21)(q26;q11), and 101.8 (4.4-210.4) in der(7)t(3;7)(q26;q21). This was similar to median %EVI1/ABL1 of 73.9 (range: 7.3-585.6) in an independent cohort of inv(3)(q21q26)/t(3;3)(q21;q26) and 67.1 (2.3-410.7) in other 3q26/EVI1 rearrangements. Healthy controls showed median EVI1 expression of 0.5 (range: 0.0-5.8). Using SNP microarray and sequencing analyses, the breakpoints of der(7)t(3;7)(q26;q21) were assigned to CDK6 and centromeric of EVI1, and of t(3;21)(q26;q11) to be within EVI1 and NRIP1. Median overall survival in patients with cryptic EVI1 rearrangements was short, comparable to patients with inv(3)(q21q26)/t(3;3)(q21;q26) or other EVI1 rearrangements. Cryptic EVI1 rearrangements contribute to explain the clinical heterogeneity of CN-AML and are associated with elevated EVI1 expression and an unfavorable prognosis. Screening for cryptic EVI1 rearrangements by FISH may be particularly appropriate in CN-AML with elevated EVI1 expression or in AML/MDS patients with chromosome 7 abnormalities.
authors.affiliation: MLL Munich Leukemia Laboratory, Munich, Germany. claudia.haferlach@mll.com
authors.forename: Claudia
authors.initials: C
authors.lastname: Haferlach
authors.forename: Ulrike
authors.initials: U
authors.lastname: Bacher
authors.forename: Vera
authors.initials: V
authors.lastname: Grossmann
authors.forename: Sonja
authors.initials: S
authors.lastname: Schindela
authors.forename: Melanie
authors.initials: M
authors.lastname: Zenger
authors.forename: Alexander
authors.initials: A
authors.lastname: Kohlmann
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Kern
authors.forename: Torsten
authors.initials: T
authors.lastname: Haferlach
authors.forename: Susanne
authors.initials: S
authors.lastname: Schnittger
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002869:Chromosome Aberrations; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics; D015331:Cohort Studies; D003582:Cytogenetics; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007621:Karyotyping; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000074008:MDS1 and EVI1 Complex Locus Protein; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D011519:Proto-Oncogenes / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014178:Translocation, Genetic
chemical_list: D004268:DNA-Binding Proteins; D000074008:MDS1 and EVI1 Complex Locus Protein; C063575:MECOM protein, human; D014157:Transcription Factors