title: ETV6/RUNX1-positive relapses evolve from an ancestral clone and frequently acquire deletions of genes implicated in glucocorticoid signaling.
abstract: Approximately 25% of childhood acute lymphoblastic leukemias carry the ETV6/RUNX1 fusion gene. Despite their excellent initial treatment response, up to 20% of patients relapse. To gain insight into the relapse mechanisms, we analyzed single nucleotide polymorphism arrays for DNA copy number aberrations (CNAs) in 18 matched diagnosis and relapse leukemias. CNAs were more abundant at relapse than at diagnosis (mean 12.5 vs 7.5 per case; P=.01) with 5.3 shared on average. Their patterns revealed a direct clonal relationship with exclusively new aberrations at relapse in only 21.4%, whereas 78.6% shared a common ancestor and subsequently acquired distinct CNA. Moreover, we identified recurrent, mainly nonoverlapping deletions associated with glucocorticoid-mediated apoptosis targeting the Bcl2 modifying factor (BMF) (n=3), glucocorticoid receptor NR3C1 (n=4), and components of the mismatch repair pathways (n=3). Fluorescence in situ hybridization screening of additional 24 relapsed and 72 nonrelapsed ETV6/RUNX1-positive cases demonstrated that BMF deletions were significantly more common in relapse cases (16.6% vs 2.8%; P=.02). Unlike BMF deletions, which were always already present at diagnosis, NR3C1 and mismatch repair aberrations prevailed at relapse. They were all associated with leukemias, which poorly responded to treatment. These findings implicate glucocorticoid-associated drug resistance in ETV6/RUNX1-positive relapse pathogenesis and therefore might help to guide future therapies.
authors.affiliation: Children's Cancer Research Institute, St Anna Kinderkrebsforschung, Vienna, Austria.
authors.forename: Lilian
authors.initials: L
authors.lastname: Kuster
authors.forename: Reinhard
authors.initials: R
authors.lastname: Grausenburger
authors.forename: Gerhard
authors.initials: G
authors.lastname: Fuka
authors.forename: Ulrike
authors.initials: U
authors.lastname: Kaindl
authors.forename: Gerd
authors.initials: G
authors.lastname: Krapf
authors.forename: Andrea
authors.initials: A
authors.lastname: Inthal
authors.forename: Georg
authors.initials: G
authors.lastname: Mann
authors.forename: Maximilian
authors.initials: M
authors.lastname: Kauer
authors.forename: Johannes
authors.initials: J
authors.lastname: Rainer
authors.forename: Reinhard
authors.initials: R
authors.lastname: Kofler
authors.forename: Andrew
authors.initials: A
authors.lastname: Hall
authors.forename: Markus
authors.initials: M
authors.lastname: Metzler
authors.forename: Lüder Hinrich
authors.initials: LH
authors.lastname: Meyer
authors.forename: Claus
authors.initials: C
authors.lastname: Meyer
authors.forename: Jochen
authors.initials: J
authors.lastname: Harbott
authors.forename: Rolf
authors.initials: R
authors.lastname: Marschalek
authors.forename: Sabine
authors.initials: S
authors.lastname: Strehl
authors.forename: Oskar A
authors.initials: OA
authors.lastname: Haas
authors.forename: Renate
authors.initials: R
authors.lastname: Panzer-Grümayer
mesh_terms: D020137:Base Pair Mismatch / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D002999:Clone Cells; D050676:Core Binding Factor Alpha 2 Subunit; D056915:DNA Copy Number Variations / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D017353:Gene Deletion; D015329:Gene Rearrangement, T-Lymphocyte / Q000235:genetics; D005938:Glucocorticoids / Q000378:metabolism*; D006801:Humans; D007223:Infant; D008297:Male; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000175:diagnosis / Q000235:genetics; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D012008:Recurrence; D015398:Signal Transduction / Q000235:genetics*; D000097764:ETS Translocation Variant 6 Protein
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D005938:Glucocorticoids; D015514:Oncogene Proteins, Fusion; D011965:Receptors, Glucocorticoid; C102421:TEL-AML1 fusion protein; D000097764:ETS Translocation Variant 6 Protein