The role of the loss of CDKN2A gene on prognosis in adult BCR-ABL1-positive acute lymphoblastic leukemia (ALL)

Background: Loss of CDKN2A/B has been associated with poorer survival and higher leukemia-initiating-cell-frequency in xenograft models (Notta F et al. Nature 2011). Here, we aimed to: a) explore the frequency and size of deletions in CDKN2A/B genes in adult BCR-ABL1-positive ALL patients; b) determine the main mechanism of inactivation; c) investigate their prognostic role. Methods: 112 patients were analyzed: 82 (73%) de novo cases, 11 (10%) unpaired relapse cases, 19 (17%) diagnosis-relapse matched samples. Affymetrix single nucleotide polymorphism (SNP) arrays (GeneChip® Human Mapping 250K NspI and Genome-Wide Human SNP 6.0) were used to identify at a high resolution copy number changes; gene-expression profiling (Affymetrix Human Exon 1ST Array) was performed to draw a specific signature associated with deletions. Results: At diagnosis, CDKN2A and CDKN2B deletions were identified in 29% and 24% of patients, respectively. Deletions were monoallelic in 72% of cases and in 43% of them the minimal overlapping region of the lost area spanned only the CDKN2A/ B genes. In contrast, in 57% of cases the loss was considerable larger and extended sometimes over the entire short arm. Analysis of the genomic status at the relapse showed a marked increase in the detection rate of CDKN2A loss (47%) compared to diagnosis (p = 0.06). The mutation screening, performed by PCR amplification and subsequent sequencing on each exon of ARF/CDKN2A/B, showed that missense point mutations are rare with only the identification of D146N in the CDKN2A exon 2 in one case. Correlation with clinical features demonstrated that deletions of CDKN2A/B are significantly associated with poor outcome both in terms of disease free-survival (p=0.001) and cumulative incidence of relapse (p=0.001). Conclusions: Novel treatment strategies targeting the ARF-MDM2-p53 pathway or CDK4/6 may be effective in this subset of patients to overcome aggressive growth properties and in vitro studies are ongoing to confirm this hypothesis. Supported by: ELN, AIL, AIRC, Fondazione Del Monte di Bologna e Ravenna, FIRB 2006, Ateneo RFO grants, Project of integreted program, Programma di Ricerca Regione – Università 2007 – 2009.