Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia

Abstract

Chromosomal aberrations are a hallmark of acute lymphoblastic leukaemia (ALL) but alone fail to induce leukaemia. To identify cooperating oncogenic lesions, we performed a genome-wide analysis of leukaemic cells from 242 paediatric ALL patients using high-resolution, single-nucleotide polymorphism arrays and genomic DNA sequencing. Our analyses revealed deletion, amplification, point mutation and structural rearrangement in genes encoding principal regulators of B lymphocyte development and differentiation in 40% of B-progenitor ALL cases. The PAX5 gene was the most frequent target of somatic mutation, being altered in 31.7% of cases. The identified PAX5 mutations resulted in reduced levels of PAX5 protein or the generation of hypomorphic alleles. Deletions were also detected in TCF3 (also known as E2A), EBF1, LEF1, IKZF1 (IKAROS) and IKZF3 (AIOLOS). These findings suggest that direct disruption of pathways controlling B-cell development and differentiation contributes to B-progenitor ALL pathogenesis. Moreover, these data demonstrate the power of high-resolution, genome-wide approaches to identify new molecular lesions in cancer.

Absence of biallelic TCRγ deletion predicts induction failure and poorer outcomes in childhood T‐cell acute lymphoblastic leukemia

“…The same is true for precursor B-cell ALL. Although PAX5 alterations are the most frequent genetic abnormality in precursor B-cell ALL [40], the loss of PAX5 is not associated with poor outcomes, possibly because of a lack of deregulation in stem cell-associated genes [41]. In contrast, deletion or sequence mutation of the IKZF1 gene, encoding the early lymphoid transcription factor Ikaros, increases the risk of treatment failure [42][43][44][45].…”

Targeting the PI3K/AKT/mTOR Signaling Axis in Children with Hematologic Malignancies

“…Recently, using modern genomic techniques, a number of potentially targetable genetic alterations have been identified in a wide variety of signaling pathways, including Jak/Stat, Ras/Raf/Mek/Erk, TP53/RB, and the PI3K/AKT/mTOR pathway. [121][122][123][124] While novel agents targeting these pathways are unlikely to cure ALL individually, the addition of targeted agents to multi-agent cytotoxic backbones has the potential to significantly improve cure rates, as evidenced by markedly improved survival in Ph+ ALL patients when the BCR-ABL kinase inhibitor imatinib was added to a multi-agent chemotherapy backbone. [1] The PI3K/AKT/mTOR pathway can be dysregulated in ALL patients by a number of mechanisms.…”

Deletions of IKZF1 and SPRED1 are associated with poor prognosis in a population-based series of pediatric B-cell precursor acute lymphoblastic leukemia diagnosed between 1992 and 2011

“…[28][29][30][31] Among the other recurrent gene targets, most -CDKN2A, EBF1, ETV6, IKZF1, PAX5, RAG1, and TBL1XR1 -have been thoroughly discussed previously. 17,19,27,32,33 However, three of the presently identified gene targets, ADD3, ATP10A and PAN3, have been less emphasized in previous studies. ADD3 plays an important role in the skeletal organization of the cell membrane in erythrocytes, 34 ATP10A is an aminophospholipid translocase responsible for transporting amphipathic molecules, 35 and PAN3 is involved in degradation of poly(A) tails in cytoplasmic mRNA.…”

“…EBF1 is a transcription factor that plays a central role in development of normal B-cells and aberrations of this gene are clearly involved in the leukemogenic process. 13,27,46 High age and deletions of IKZF1 and SPRED1 were also significantly associated with a poor 10-yr OS (Figure 3). The present finding that deletions of SPRED1 are recurrent and that they provide a negative prognostic impact in BCP ALL is clinically important, not least considering that SPRED1 is part of MAPK signaling and that inhibitors of this pathway currently are undergoing clinical trials and hence may be novel therapeutic options.…”

“…25 Although these genes have not been reported to be deleted in ALL or otherwise associated with this disease, the observed 6p imbalances overlap to some extent with 6p deletions reported in Down syndrome-associated ALL and other histone clusters on 6p have been shown be deleted in pediatric ALL, with methylation arrays suggesting that histone deletions are associated with methylation alterations. 26,27 Thus, HIST1H2BD and HIST1H1E may be added to the growing list of acute leukemia-associated genes, for example DNMT3, EZH2, HOX family, and MLL, that 13 contribute to the leukemogenic process through deregulated CpG methylation or histone modification. [28][29][30][31] Among the other recurrent gene targets, most -CDKN2A, EBF1, ETV6, IKZF1, PAX5, RAG1, and TBL1XR1 -have been thoroughly discussed previously.…”