By genome-wide analyses of DNA copy number abnormalities in adult BCR-ABL1-positive ALL patients (pts) using single nucleotide polymorphism (SNP) microarrays (Affymetrix 500K and SNP 6.0), we identified a high frequency of genetic alterations of regulators of B lymphoid development (PAX5, EBF1, IKZF1)and cell cycle (CDKN2A, CDKN2B, BTG1). The most frequent somatic copy number alteration was deletion on 7p12 of IKZF1 (68/106 patients, 64%), which encodes the transcription factor Ikaros required for the earliest stages of lymphoid lineage commitment. Here, we characterized and mapped all breakpoints in IKZF1 gene to recognize that two major deletions occur in BCR-ABL1-positive ALL: type A characterized by loss of exons 4-7 (44%) and due to breakpoints occurring in introns 3 and 7; type B characterized by removal of exons 2-7 (19%) and due to a variable pattern of breakpoints in introns 1 and 7. In two pts we had both \#916;2-7 and \#916;4-7 deletions and in one we identified a deletion of all IKZF1 gene and part of GRB10. A variable number of nucleotides (patient-specific) were inserted at the conjunction and maintained with fidelity at the time of relapse. The extent of both deletions correlated with the expression of dominant-negative isoforms with cytoplasmatic localization. The IKZF1 alteration was also identified in B-negative ALL pts (41%) and at the progression of CML to lymphoid blast crisis (66%), but never in myeloid blast crisis CML and chronic phase CML. Known DNA sequences were mapped along the breakpoint cluster regions including heptamer recombination signal sequences recognized by the RAG enzymes during V(D)J recombination and activation-induced cytidine deaminase (AID) consensus motifs (DGYW/WRCH). Gene expression profiling analysis of pts with IKZF1 deletion vs wild-type pts identified a unique signature characterized by a down-regulation of genes involved in pre-B-cell differentiation (e.g. VPREB1, VPREB3, IGLL3, BLK), demonstrating that genomic IKZF1 alterations have a strong impact on trascriptoma and contribute to an impaired B-cell differentiation. Univariate analysis showed that the IKZF1 deletion is a negative prognostic marker influencing the cumulative incidence of relapse (10.1 months for pts with deletion vs 56.1 months for wild-type pts, p=0.0103) and disease-free survival (DFS) (10.1 months vs 32.1 months, respectively, p=0.0229). The negative prognostic impact of the IKZF1 deletion on DFS was also confirmed by multivariate analysis (p=0.0445). In conclusion, deletion of IKZF1 is an important event in the development of BCR-ABL1 B-progenitor ALL which significantly influences clinical outcome. Supported by: European LeukemiaNet, AIL, AIRC, FIRB 2006, Fondazione del Monte di Bologna e Ravenna, Strategico di Ateneo, GIMEMA Onlus.
Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 1287.
100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO