Recent genome-wide analyses in B-ALL have identified a high frequency of DNA copy-number abnormalities, but the biological and prognostic implications of these abnormalities have not been defined. In order to address this issue, a cohort of 149 adult ALL patients (106 BCR-ABL1-postive, 3 ALL1/AF4, 1 EA/PBX, 39 negative for known molecular rearrangements) were analyzed with the use of singlenucleotide– polymorphism (SNP) microarrays (Affymetrix 250K NspI and SNP6.0), FISH, transcriptional profiling, and resequencing of samples obtained at diagnosis. Lesions varied from loss or gain of complete chromosome arms (trisomy 4, monosomy 7, loss of 9p, gain of 1q) to micro-alterations targeting genomic intervals in which the minimal common region of change involved one or few genes. Lesions in genes involved in early B-cell differentiation (60%) and cell cycle regulation (40%) were observed with relatively high frequency (60%). The most frequent somatic copy number alteration was deletion on 7p12 of IKZF1 (75% in BCR-ABL1 positive and 58% in BCR-ABL1-negative ALL), which encodes the transcription factor Ikaros required for the earliest stages of lymphoid lineage commitment. FISH analysis using a pool of fosmid probes for IKZF1 and genomic quantitative PCR confirmed SNP results. Among the 149 patients, the entire IKZF1 locus was deleted in 19 (13%); in 84 (56%) additional patients, a subgroup of exons or the genomic region immediately upstream of IKZF1 was deleted. In 48 of them, there was a deletion of coding exons 4 through 7, which results in expression of a dominant-negative isoform, Ik6, which cytoplasmatic localization. Using gene-set enrichment analysis to compare the geneexpression signatures of patients with IKZF1 deletion versus not-deleted patients, we identified a unique signatures independent by BCRABL1 and characterized by down-regulation of B-cell lineage genes (e.g. VPREB1, VPREB3, IGLL3, BLK) and up-regulation of genes involved in cell-cycle progression (STK17B, SERPINB9, CDKN1A). We next investigated whether the IKZF1 deletions associated with a poor outcome. Univariate analysis showed that the IKZF1 deletion negatively influenced the cumulative incidence of relapse (p=0.0103) and disease-free survival (p=0.0229). Conclusion. Deletion of IKZF1 is an important event in the development of B-progenitor ALL which significantly influences clinical outcome. European LeukemiaNet, AIL, AIRC, FIRB 2006, Strategico di Ateneo, GIMEMA Onlus.
IKZF1 (IKAROS) DELETIONS ARE INDEPENDENT ON THE PHILADELPHIA CHROMOSOME AND ARE ASSOCIATED WITH AN IMPAIRED B-CELL DIFFERENTIATION AND POOR OUTCOME IN ACUTE LYMPHOBLASTIC LEUKEMIA PATIENTS
IACOBUCCI, ILARIA;LONETTI, ANNALISA;BALDAZZI, CARMEN;PAPAYANNIDIS, CRISTINA;SOVERINI, SIMONA;PAOLINI, STEFANIA;MARTINELLI, GIOVANNI
2009
Abstract
Recent genome-wide analyses in B-ALL have identified a high frequency of DNA copy-number abnormalities, but the biological and prognostic implications of these abnormalities have not been defined. In order to address this issue, a cohort of 149 adult ALL patients (106 BCR-ABL1-postive, 3 ALL1/AF4, 1 EA/PBX, 39 negative for known molecular rearrangements) were analyzed with the use of singlenucleotide– polymorphism (SNP) microarrays (Affymetrix 250K NspI and SNP6.0), FISH, transcriptional profiling, and resequencing of samples obtained at diagnosis. Lesions varied from loss or gain of complete chromosome arms (trisomy 4, monosomy 7, loss of 9p, gain of 1q) to micro-alterations targeting genomic intervals in which the minimal common region of change involved one or few genes. Lesions in genes involved in early B-cell differentiation (60%) and cell cycle regulation (40%) were observed with relatively high frequency (60%). The most frequent somatic copy number alteration was deletion on 7p12 of IKZF1 (75% in BCR-ABL1 positive and 58% in BCR-ABL1-negative ALL), which encodes the transcription factor Ikaros required for the earliest stages of lymphoid lineage commitment. FISH analysis using a pool of fosmid probes for IKZF1 and genomic quantitative PCR confirmed SNP results. Among the 149 patients, the entire IKZF1 locus was deleted in 19 (13%); in 84 (56%) additional patients, a subgroup of exons or the genomic region immediately upstream of IKZF1 was deleted. In 48 of them, there was a deletion of coding exons 4 through 7, which results in expression of a dominant-negative isoform, Ik6, which cytoplasmatic localization. Using gene-set enrichment analysis to compare the geneexpression signatures of patients with IKZF1 deletion versus not-deleted patients, we identified a unique signatures independent by BCRABL1 and characterized by down-regulation of B-cell lineage genes (e.g. VPREB1, VPREB3, IGLL3, BLK) and up-regulation of genes involved in cell-cycle progression (STK17B, SERPINB9, CDKN1A). We next investigated whether the IKZF1 deletions associated with a poor outcome. Univariate analysis showed that the IKZF1 deletion negatively influenced the cumulative incidence of relapse (p=0.0103) and disease-free survival (p=0.0229). Conclusion. Deletion of IKZF1 is an important event in the development of B-progenitor ALL which significantly influences clinical outcome. European LeukemiaNet, AIL, AIRC, FIRB 2006, Strategico di Ateneo, GIMEMA Onlus.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
