Combined high-resolution array-based comparative genomic hybridization and expression profiling of ETV6/RUNX1-positive acute lymphoblastic leukemias reveal a high incidence of cryptic Xq duplications and identify several putative target genes within the commonly gained region

Abstract

Seventeen ETV6/RUNX1-positive pediatric acute lymphoblastic leukemias were investigated by high-resolution array-based comparative genomic hybridization (array CGH), gene expression profiling and fluorescence in situ hybridization. Comparing the array CGH and gene expression patterns revealed that genomic imbalances conferred a great impact on the expression of genes in the affected regions. The array CGH analyses identified a high frequency of cytogenetically cryptic genetic changes, for example, del(9p) and del(12p). Interestingly, a duplication of Xq material, varying between 30 and 60 Mb in size, was found in 6 of 11 males (55%), but not in females. Genes on Xq were found to have a high expression level in cases with dup(Xq); a similar overexpression was confirmed in t(12;21)-positive cases in an external gene expression data set. By studying the expression profile and the proposed function of genes in the minimally gained region, several candidate target genes (SPANXB, HMGB3, FAM50A, HTATSF1 and RAP2C) were identified. Among them, the testis-specific SPANXB gene was the only one showing a high and uniform overexpression, irrespective of gender and presence of Xq duplication, suggesting that this gene plays an important pathogenetic role in t(12;21)-positive leukemia.

Genome-wide profiling of genetic alterations in acute lymphoblastic leukemia: recent insights and future directions

“…22,23,[25][26][27][28][29][30][31][32][33][34][35]42 These studies have delineated regions of deletion (for example, ETV6 in B-ALL), have mapped translocation breakpoints, 25,30 have identified new CNA (for example, 9q34 duplication in T-ALL), 27 and characterized large and/or complex alterations (for example, gains of 1q and intrachromosomal amplification of chromosome 21 in B-ALL). 26,28 However, the superior resolution of oligonucleotide array platforms, such as SNP arrays, has enabled a more detailed and comprehensive characterization of genetic alterations in ALL.…”

BCR-ABL1 gene rearrangement as a subclonal change in ETV6-RUNX1–positive B-cell acute lymphoblastic leukemia

“…These genes are of many different classes and include genes encoding proteins involved in the cell cycle checkpoint pathway (ATM), cell cycle control (CDKN1B and CEBPA), and tumor suppression (CDKN2A, MTAP, and RB1), to name a few. 5,7,12,[14][15][16][17][18] Our patient showed a number of the common ETV6-RUNX1-positive secondary changes in the primary clone; namely, trisomy of chromosome 21 and deletion of both 6q and 11q. These abnormalities likely represent the required second genomic hit that initiated B-ALL in our patient.…”

“…10 There are an increasing number of common secondary abnormalities in ETV6-RUNX1-positive B-ALL that may be observed by conventional or molecular cytogenetics methods (Table 1). 5,7,10,12,[14][15][16][17][18] The vast majority of secondary abnormalities are genomic losses, with the ratio of deletion to duplication being 2:1. 18 Secondary chromosome abnormalities are detected in up to 85% of ETV6-RUNX1-positive cases.…”

“…The most common findings are abnormalities of 12p (39%), with deletion of the ETV6 allele on the chromosome 12 not involved in the t(12;21) usually affected. 5,7,10,12,[14][15][16][17] Another common secondary change is gain of chromosome 21, seen in up to 25% of cases. Typically, the gain is of a normal chromosome 21 (70%), with a portion showing a gain of the der(21)t(12;21)(p13;q22) (30%).…”

“…10 Abnormalities of 9p are seen in up to 25% of cases, and this includes cytogenetically visible deletions and submicroscopic copy number changes typically involving the tumor suppressor CDKN2A/CDKN2B and the B-cell differentiation regulator PAX5. 5,10,[12][13][14][15][16][17] An increasing number of submicroscopic changes have been shown to occur at relatively high frequency in ETV6-RUNX1-positive B-ALL by microarray techniques, and a number of putative causative genes have been identified. These genes are of many different classes and include genes encoding proteins involved in the cell cycle checkpoint pathway (ATM), cell cycle control (CDKN1B and CEBPA), and tumor suppression (CDKN2A, MTAP, and RB1), to name a few.…”