Etv6/Runx1-Positiverelapsesevolvefromanancestralcloneandfrequently Acquiredeletionsofgenesimplicatedinglucocorticoidsignaling

9445 Words Oct 11th, 2014 38 Pages
LYMPHOID NEOPLASIA

ETV6/RUNX1-positive relapses evolve from an ancestral clone and frequently acquire deletions of genes implicated in glucocorticoid signaling
Lilian Kuster,1 Reinhard Grausenburger,1 Gerhard Fuka,1 Ulrike Kaindl,1 Gerd Krapf,1 Andrea Inthal,1 Georg Mann,2 Maximilian Kauer,1 Johannes Rainer,3 Reinhard Kofler,3 Andrew Hall,4 Markus Metzler,5 Luder Hinrich Meyer,6 Claus Meyer,7 ¨ Jochen Harbott,8 Rolf Marschalek,7 Sabine Strehl,1 Oskar A. Haas,2 and Renate Panzer-Grumayer1,2 ¨
Cancer Research Institute, St Anna Kinderkrebsforschung, Vienna, Austria; 2St Anna Kinderspital, Vienna, Austria; 3Tyrolean Cancer Research Institute and Biocenter - Division Molecular Pathophysiology, Innsbruck Medical University, Innsbruck,
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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. (Blood. 2011;117(9):2658-2667)

Introduction
The ETV6/RUNX1 (E/R) fusion gene (also known as TEL/AML1) results from the chromosomal translocation t(12;21) and is present in approximately 25% of childhood B-cell precursor acute lymphoblastic leukemia (BCP ALL).1 This leukemia subtype is generally associated with good prognostic parameters and excellent molecular response to treatment.2-6 Although almost all children can be treated successfully, predominantly late relapses occur nevertheless in up to 20% of the patients.7-9 In the multistep model of E/R leukemia development, the gene fusion represents the first transforming event. It virtually always takes place during fetal development but is per se unable to generate overt disease.10,11 One of

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