Abstract 90: A cell cycle-related genomic and transcriptomic signature distinguish aneuploid and euploid acute myeloid leukemia

Chromosome gain or loss, which is the hallmark of aneuploidy, occurs in about 10% of adult Acute Myeloid Leukemia (AML) cases (Farag et al. IJO 2002, Breems et al. JCO 2008), despite inducing a dramatic reduction of cellular fitness in non-malignant cells (Torres et al. Science 2007). The study aimed to identify AML-specific molecular mechanisms having a causative and/or tolerogenic role towards aneuploidy. We performed 100 bp paired-end whole exome sequencing (WES, Illumina Hiseq2000) of 38 aneuploid (A) and 34 euploid (E) AML cases, identified according to cytogenetic analysis and SNP array (CytoScan HD, Affymetrix). Variants were called with GATK, MuTect and VarScan. We also compared the transcriptomic profile of leukemic bone marrow cells from 21 A-AML and 28 E-AML cases (HTA 2.0, Affymetrix). A-AML showed a significantly higher mutation load compared with E-AML (median number of variants: 25 and 15, respectively, p Our data show a link between aneuploidy and genomic instability in AML and highlight novel molecular mechanisms for the acquisition and/or maintenance of the aneuploid phenotype. Deregulation of the cell cycle machinery and DNA damage/repair checkpoints, either through mutations, copy number and transcriptomic alterations, cooperate with leukemogenic pathways, as KRAS signaling, to develop A-AML and overcome the unfitness barrier. This evidence suggests that a number of A-AML patients may benefit from pharmacological reactivation of TP53 and inhibition of KRAS pathway. Supported by: FP7 NGS-PTL project, ELN, AIL, AIRC, PRIN, progetto Regione-Università 2010-12 (L. Bolondi). Citation Format: Giorgia Simonetti, Antonella Padella, Marco Manfrini, ĺtalo Faria do Valle, Cristina Papayannidis, Carmen Baldazzi, Maria Chiara Fontana, Viviana Guadagnuolo, Anna Ferrari, Elisa Zago, Marianna Garonzi, Simona Bernardi, Annalisa Astolfi, Maria Chiara Abbenante, Giovanni Marconi, Elisa Zuffa, Eugenia Franchini, Ilaria Iacobucci, Michele Cavo, Emanuela Ottaviani, Nicoletta Testoni, Alberto Ferrarini, Massimo Delledonne, Torsten Haferlach, Daniel Remondini, Giovanni Martinelli. A cell cycle-related genomic and transcriptomic signature distinguish aneuploid and euploid acute myeloid leukemia. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 90.