SINGLE NUCLEOTIDE POLYMORPHISM (SNP) ARRAYS IDENTIFIED FREQUENT GENOMIC ABNORMALITIES IN GENES INVOLVED IN DRUG TRANSPORT AND INHIBITION OF APOPTOSIS IN ADULT ACUTE MYELOID LEUKEMIA PATIENTS

Introduction. Acute myeloid leukemia (AML) is a heterogeneous disease with various chromosomal aberrations. The karyotype at diagnosis provides important prognostic information that influences therapy and outcome. However, using conventional chromosome banding techniques alone, karyotype abnormalities are detected in only half of all cases. Aims. To identify novel genomic regions of interest in normal karyotype AML and to identify novel candidate regions and disease-related genes in patients with complex karyotypes using genome-wide SNP-array. Patients and methods. Samples from 70 AML patients with FAB-M0, M1, M2, M3, M4, M5, miscellaneous cytogenetic abnormalities and normal karyotype were examined by SNP arrays (Human Mapping 250K NspI and SNP6.0, Affymetrix). Fluorescence in situ hybridization, quantitative PCR and nucleotide sequencing were used to confirm genomic alterations. Results: A wide spectrum of different genetic lesions (gains/losses) involving complete chromosome arms (del 16q, i(13q10), del 3p, del 7p, monosomy 9) or submicroscopic genomic intervals were identified in a substantial proportion of cases (55%) with a prevalence of gains respect to losses. Focal genetic alterations were detected at the breakpoints of previously cytogenetically identified chromosomal translocations, such as t(2;3)(p22-23)(q26-27) and t(1;11)(p32;q23). Hemizygous deletions were identified at 2q33.3-q34 involving ERBB4 (v-erb-a erythroblastic leukemia viral oncogene homolog 4 avian), at 9p21.3- p21.2 (CDKN2A-2B), at 12p13 (ETV6), at 17q12 (NF1) and 21q21.2 (RUNX1). Most frequent gains affected the oncogene MYC at 8q24 (4.33 Mb), the ABC transporters genes at 17q24, PTPRM at 18p11 and ERG at 21q22. Other recurring genetic lesions were uncommon and were identified only in single cases. Some lesions affected regions with a single gene, such as: ETAA1, FIGN, STK32B, PRAGMIN, PCM1, GLIS3, MRGPRX1, SESN3, BCL2L14 or lacking annotated genes. Marked differences in the combination of copy number anomalies were identified across the different genetic subtypes of AML. Conclusion. These data demonstrated that, in contrast to adult acute lymphoblastic leukaemia (ALL), AML is characterized by relatively few recurring copy number alterations, and that spectrum of genetic anomalies is significantly associated with AML disease subtype. Supported by: European LeukemiaNet, AIL, AIRC, FIRB 2006, Fondazione del Monte di Bologna e Ravenna, PIO project 2007, Strategico di Ateneo.