High-resolution genomic profiling of childhood ALL reveals novel recurrent genetic lesions affecting pathways involved in lymphocyte differentiation and cell cycle progression

Abstract

Gross cytogenetic anomalies are traditionally being used as diagnostic, prognostic and therapeutic markers in the clinical management of cancer, including childhood acute lymphoblastic leukemia (ALL). Recently, it has become increasingly clear that genetic lesions driving tumorigenesis frequently occur at the submicroscopic level and, consequently, escape standard cytogenetic observations. Therefore, we profiled the genomes of 40 childhood ALLs at high resolution. We detected multiple de novo genetic lesions, including gross aneuploidies and segmental gains and losses, some of which were subtle and affected single genes. Many of these lesions involved recurrent (partially) overlapping deletions and duplications, containing various established leukemia-associated genes, such as ETV6, RUNX1 and MLL. Importantly, the most frequently affected genes were those controlling G1/S cell cycle progression (e.g. CDKN2A, CDKN1B and RB1), followed by genes associated with B-cell development. The latter group includes microdeletions of the B-lineage transcription factors PAX5, EBF, E2-2 and IKZF1 (Ikaros), as well as genes with other established roles in B-cell development, that is RAG1 and RAG2, FYN, PBEF1 or CBP/PAG. The fact that we frequently encountered multiple lesions affecting genes involved in cell cycle regulation and Bcell differentiation strongly suggests that both these processes need to be targeted independently and simultaneously to trigger ALL development.

Gfi1 and Gfi1b: key regulators of hematopoiesis

“…The control of proliferation, differentiation and survival of blood cells by Gfi1 and Gfi1b shows striking functional similarities to a set of other hematopoietic transcription factors. [97][98][99] Inherited and acquired mutations in many of these hematopoietic transcription factors cause hematological diseases. As loss of Gfi1/Gfi1b function leads to various different hematological defects in experimental settings, it is warranted to further study their contribution to human hematological disease.…”

DNA Hypermethylation of Cell Cycle (p15 and p16) and Apoptotic (p14, p53, DAPK and TMS1) Genes in Peripheral Blood of Leukemia Patients

“…In spite of the limited number of cases presented with methylation in these genes, it is possible to assume that methylation at these loci is highly selective as shown in Figure 4. Genetic abnormalities are frequent in p15 and p16 in CML (Guran et al, 1998) and ALL (Kuiper et al, 2007). In ALL patients, methylation was found to be complementary to heterozygous deletions at the 9p21 region (Novara et al, 2009) but not associated with deletion regions or with prognosis (Kim et al, 2009).…”

DNA copy-number abnormalities do not occur in infant ALL with t(4;11)/MLL-AF4

“…In fact, SNP array studies in childhood, adolescent and adult ALL indicated that different genes along the same pathway can be deleted, and that the accumulation of their abnormalities could lead to frank malignancy, [13][14][15][16] pointing to microdeletions of key genes as a general feature peculiar to BCP-ALL, shared among different Figure 2 Additional chromosomal lesion at relapses. Copy Number Analyser for GeneChip (CNAG) visualization of additional copy-number abnormality (CNA) detected in the relapse samples.…”

“…[13][14][15] These findings suggested that the direct disruption of pathway(s) controlling B-cell development and differentiation contribute to BCP (B-cell precursor) ALL pathogenesis. 13 In addition, a similar pattern of deletions was also observed in adult and adolescent ALL, 16 suggesting that microdeletions that affect key genes may be a common trademark of ALL despite age, clinical, morphological, and cytogenetic differences.…”