TY - JOUR
T1 - High-resolution genomic profiling of childhood ALL reveals novel recurrent genetic lesions affecting pathways involved in lymphocyte differentiation and cell cycle progression
AU - Kuiper, R P
AU - Schoenmakers, E F P M
AU - van Reijmersdal, S V
AU - Hehir-Kwa, J Y
AU - van Kessel, A Geurts
AU - van Leeuwen, F N
AU - Hoogerbrugge, P M
N1 - Funding Information:
We thank E-J Kamsteeg, G Merkx and I Janssen for their valuable contributions, and Drs A Simons and M Stevens-Kroef for critically reading the article. We are grateful to Dr ER van Wering from the Dutch Childhood Oncology Group and the Dutch Workgroup Cancer Genetics and Cytogenetics (NWKGC) for material and scientific interactions. This work was supported by the Dutch Cancer Foundation and KiKa.
PY - 2007/6
Y1 - 2007/6
N2 - 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 B-cell differentiation strongly suggests that both these processes need to be targeted independently and simultaneously to trigger ALL development.
AB - 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 B-cell differentiation strongly suggests that both these processes need to be targeted independently and simultaneously to trigger ALL development.
KW - B-Lymphocytes/cytology
KW - Cell Cycle/genetics
KW - Cell Differentiation/genetics
KW - Chromosome Aberrations
KW - Female
KW - Gene Dosage
KW - Gene Expression Profiling/methods
KW - Genes, Neoplasm
KW - Genomics/methods
KW - Humans
KW - Lymphocytes/cytology
KW - Male
KW - Nucleic Acid Hybridization
KW - Precursor Cell Lymphoblastic Leukemia-Lymphoma/etiology
KW - Transcription Factors
UR - http://www.scopus.com/inward/record.url?scp=34249733805&partnerID=8YFLogxK
U2 - 10.1038/sj.leu.2404691
DO - 10.1038/sj.leu.2404691
M3 - Article
C2 - 17443227
SN - 0887-6924
VL - 21
SP - 1258
EP - 1266
JO - Leukemia
JF - Leukemia
IS - 6
ER -