151. GENOME-WIDE SCREENING OF CHRONIC MYELOID LEUKEMIA PATIENTS BY SNP ARRAYS: ALTERATIONS ASSOCIATED WITH DISEASE PROGRESSION
- Author
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Colarossi, S., Gnani, A., Soverini, S., Castagnetti, F., Marzocchi, G., Luatti, S., Astolfi, A., Formica, S., Palandri, F., Poerio, A., Rosti, G., Testoni, N., Baccarani, M., Martinelli, G., IACOBUCCI, ILARIA, LONETTI, ANNALISA, AMABILE, MARILINA, PESSION, ANDREA, Colarossi, S., Gnani, A., Soverini, S., Castagnetti, F., Marzocchi, G., Luatti, S., Astolfi, A., Formica, S., Iacobucci, I., Lonetti, A., Palandri, F., Poerio, A., Amabile, M., Rosti, G., Pession, A., Testoni, N., Baccarani, M., and Martinelli, G.
- Subjects
SNP ARRAYS ,CHRONIC MYELOID LEUKEMIA (CML) - Abstract
Background. The expression of BCR-ABL gene in Chronic Myeloid Leukemia (CML) is necessary for malignant transformation but the biologic basis of the progression from Chronic Phase (CP) to Blast Crisis (BC) is poorly understood. Aim. Identifying the genomic imbalances involved in the transition into BC, before clinical features, may provide diagnostic markers of progression; so we used SNP arrays to perform a high-resolution mapping of BC CML patients genomes. Methods. We analyzed 11 patients affected by BC CML disease. Genomic DNA were extracted from bone marrow or peripheral blood mononuclear cells archived both at the time of diagnosis and progression. SNP array-based karyotyping was carried out using Affymetrix GeneChip Human Mapping arrays. Copy number (CN) analysis was performed using Hapmap normal individuals as reference set and two different softwares. Results. After exclusion of genomic copy number variations (CNVs), the following results were achieved: five patients showed huge amplifications and deletions, ranging from 30Mb to 160Mb, on chromosomes 9, 7, 3 and 6. We also found several heterozygous micro-deletions and micro-amplifications spreading all over the genome. This analysis has identified abnormalities in genes involved in apoptosis (e.g., GADD45A, FOXO3A, GAS6), DNA damage response (e.g., MYST as known as Hmof, XRCC2), tumor suppression (e.g., C/EBPdelta, LATS1), chromatin regulation (e.g., HDAC9), and genes belonged to ABC transporters (e.g., ABCB1), ras family and transcriptional/translational factors (e.g., ETV1). Moreover were found copy number changes (gain/loss) in genes associated with malignancy, in particular TNFRSF17, MET, IGFBPL1, EVI1, PTENP1. Other alterations affected key pathways including cell cycle regulation and WNT signaling. Conclusions. The use of the genomic tool Genome-Wide Human SNP array allowed us to identify, at submicroscopic level, genetic lesions in patients affected by CML in BC. Our results will be further validated by real-time PCR for the altered genes involved key pathways, while sequencing and mutation analysis will be performed on the remaining allele of putative tumor suppressor genes to identify their residual activity. All these validations and the increased number of analyzed patients will provide new insights into the genetic profiling that lead disease progression from CP to BC and consequently new opportunities to develop specific target therapies.
- Published
- 2009