Global Genomic Characterization of Acute Lymphoblastic Leukemia

Overview

Journal Semin Hematol

Specialty Hematology

Date 2008 Dec 23

PMID 19100363

Citations 29

Authors

Charles G Mullighan

James R Downing

Affiliations

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Abstract

A key goal in cancer research is to identify the total complement of genetic and epigenetic alterations that contribute to tumorigenesis. We are currently witnessing the rapid evolution and convergence of multiple genome-wide platforms that are making this goal a reality. Leading this effort are studies of the molecular lesions that underlie pediatric acute lymphoblastic leukemia (ALL). The recent application of microarray-based analyses of DNA copy number abnormalities (CNAs) in pediatric ALL, complemented by transcriptional profiling, resequencing and epigenetic approaches, has identified a high frequency of common genetic alterations in both B-progenitor and T-lineage ALL. These approaches have identified abnormalities in key pathways, including lymphoid differentiation, cell cycle regulation, tumor suppression, and drug responsiveness. Moreover, the nature and frequency of CNAs differ markedly among ALL genetic subtypes. In this article, we review the key findings from the published data on genome-wide analyses of ALL and highlight some of the technical aspects of data generation and analysis that must be carefully controlled to obtain optimal results.

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References

Beroukhim R, Lin M, Park Y, Hao K, Zhao X, Garraway L . Inferring loss-of-heterozygosity from unpaired tumors using high-density oligonucleotide SNP arrays. PLoS Comput Biol. 2006; 2(5):e41. PMC: 1458964. DOI: 10.1371/journal.pcbi.0020041. View

Pinkel D, Albertson D . Comparative genomic hybridization. Annu Rev Genomics Hum Genet. 2005; 6:331-54. DOI: 10.1146/annurev.genom.6.080604.162140. View

Pui C, Sandlund J, Pei D, Campana D, Rivera G, Ribeiro R . Improved outcome for children with acute lymphoblastic leukemia: results of Total Therapy Study XIIIB at St Jude Children's Research Hospital. Blood. 2004; 104(9):2690-6. DOI: 10.1182/blood-2004-04-1616. View

Iafrate A, Feuk L, Rivera M, Listewnik M, Donahoe P, Qi Y . Detection of large-scale variation in the human genome. Nat Genet. 2004; 36(9):949-51. DOI: 10.1038/ng1416. View

Lee H, Cha S, Lee M, Cho G, Choi W, Suk K . Role of antiproliferative B cell translocation gene-1 as an apoptotic sensitizer in activation-induced cell death of brain microglia. J Immunol. 2003; 171(11):5802-11. DOI: 10.4049/jimmunol.171.11.5802. View

Van Vlierberghe P, Meijerink J, Lee C, Ferrando A, Look A, van Wering E . A new recurrent 9q34 duplication in pediatric T-cell acute lymphoblastic leukemia. Leukemia. 2006; 20(7):1245-53. DOI: 10.1038/sj.leu.2404247. View

Fielding A, Richards S, Chopra R, Lazarus H, Litzow M, Buck G . Outcome of 609 adults after relapse of acute lymphoblastic leukemia (ALL); an MRC UKALL12/ECOG 2993 study. Blood. 2006; 109(3):944-50. DOI: 10.1182/blood-2006-05-018192. View

Winandy S, Wu P, Georgopoulos K . A dominant mutation in the Ikaros gene leads to rapid development of leukemia and lymphoma. Cell. 1995; 83(2):289-99. DOI: 10.1016/0092-8674(95)90170-1. View

Andreasson P, Schwaller J, Anastasiadou E, Aster J, Gilliland D . The expression of ETV6/CBFA2 (TEL/AML1) is not sufficient for the transformation of hematopoietic cell lines in vitro or the induction of hematologic disease in vivo. Cancer Genet Cytogenet. 2001; 130(2):93-104. DOI: 10.1016/s0165-4608(01)00518-0. View

10.

Ogawa S, Hangaishi A, Miyawaki S, Hirosawa S, Miura Y, Takeyama K . Loss of the cyclin-dependent kinase 4-inhibitor (p16; MTS1) gene is frequent in and highly specific to lymphoid tumors in primary human hematopoietic malignancies. Blood. 1995; 86(4):1548-56. View

11.

Clappier E, Cuccuini W, Kalota A, Crinquette A, Cayuela J, Dik W . The C-MYB locus is involved in chromosomal translocation and genomic duplications in human T-cell acute leukemia (T-ALL), the translocation defining a new T-ALL subtype in very young children. Blood. 2007; 110(4):1251-61. DOI: 10.1182/blood-2006-12-064683. View

12.

Campbell P, Stephens P, Pleasance E, OMeara S, Li H, Santarius T . Identification of somatically acquired rearrangements in cancer using genome-wide massively parallel paired-end sequencing. Nat Genet. 2008; 40(6):722-9. PMC: 2705838. DOI: 10.1038/ng.128. View

13.

Weng A, Ferrando A, Lee W, Morris 4th J, Silverman L, Sanchez-Irizarry C . Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science. 2004; 306(5694):269-71. DOI: 10.1126/science.1102160. View

14.

Lahortiga I, De Keersmaecker K, Van Vlierberghe P, Graux C, Cauwelier B, Lambert F . Duplication of the MYB oncogene in T cell acute lymphoblastic leukemia. Nat Genet. 2007; 39(5):593-5. DOI: 10.1038/ng2025. View

15.

Mullighan C, Miller C, Radtke I, Phillips L, Dalton J, Ma J . BCR-ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros. Nature. 2008; 453(7191):110-4. DOI: 10.1038/nature06866. View

16.

Kawamata N, Ogawa S, Zimmermann M, Kato M, Sanada M, Hemminki K . Molecular allelokaryotyping of pediatric acute lymphoblastic leukemias by high-resolution single nucleotide polymorphism oligonucleotide genomic microarray. Blood. 2007; 111(2):776-84. PMC: 2200831. DOI: 10.1182/blood-2007-05-088310. View

17.

Nakase K, Ishimaru F, Avitahl N, Dansako H, Matsuo K, Fujii K . Dominant negative isoform of the Ikaros gene in patients with adult B-cell acute lymphoblastic leukemia. Cancer Res. 2000; 60(15):4062-5. View

18.

Kitagawa Y, Inoue K, Sasaki S, Hayashi Y, Matsuo Y, Lieber M . Prevalent involvement of illegitimate V(D)J recombination in chromosome 9p21 deletions in lymphoid leukemia. J Biol Chem. 2002; 277(48):46289-97. DOI: 10.1074/jbc.M208353200. View

19.

Williams R, Roussel M, Sherr C . Arf gene loss enhances oncogenicity and limits imatinib response in mouse models of Bcr-Abl-induced acute lymphoblastic leukemia. Proc Natl Acad Sci U S A. 2006; 103(17):6688-93. PMC: 1440588. DOI: 10.1073/pnas.0602030103. View

20.

ONeil J, Grim J, Strack P, Rao S, Tibbitts D, Winter C . FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to gamma-secretase inhibitors. J Exp Med. 2007; 204(8):1813-24. PMC: 2118656. DOI: 10.1084/jem.20070876. View