Abstract
AbstractStructural and numerical alterations of chromosome 21 are extremely common in hematological malignancies. While the functional impact of chimeric transcripts from fused chromosome 21 genes such as TEL-AML1, AML1-ETO, or FUS-ERG have been extensively studied, the role of gain of chromosome 21 remains largely unknown. Gain of chromosome 21 is a frequently occurring aberration in several types of acute leukemia and can be found in up to 35% of cases. Children with Down syndrome (DS), who harbor constitutive trisomy 21, highlight the link between gain of chromosome 21 and leukemogenesis, with an increased risk of developing acute leukemia compared with other children. Clinical outcomes for DS-associated leukemia have improved over the years through the development of uniform treatment protocols facilitated by international cooperative groups. The genetic landscape has also recently been characterized, providing an insight into the molecular pathogenesis underlying DS-associated leukemia. These studies emphasize the key role of trisomy 21 in priming a developmental stage and cellular context susceptible to transformation, and have unveiled its cooperative function with additional genetic events that occur during leukemia progression. Here, using DS-leukemia as a paradigm, we aim to integrate our current understanding of the role of trisomy 21, of critical dosage-sensitive chromosome 21 genes, and of associated mechanisms underlying the development of hematological malignancies. This review will pave the way for future investigations on the broad impact of gain of chromosome 21 in hematological cancer, with a view to discovering new vulnerabilities and develop novel targeted therapies to improve long term outcomes for DS and non-DS patients.
Funder
Cancéropôle Ile-de-France, Fondation pour la Recherche Médicale
Publisher
Springer Science and Business Media LLC
Subject
Oncology,Cancer Research,Hematology
Reference146 articles.
1. Mitelman F, Heim S, Mandahl N. Trisomy 21 in neoplastic cells. Am J Med Genet. 1990;7(Suppl.):262–6.
2. Duijf PH, Schultz N, Benezra R. Cancer cells preferentially lose small chromosomes. Int J Cancer. 2013;132:2316–26.
3. Raimondi SC, Chang MN, Ravindranath Y, Behm FG, Gresik MV, Steuber CP, et al. Chromosomal abnormalities in 478 children with acute myeloid leukemia: clinical characteristics and treatment outcome in a cooperative pediatric oncology group study-POG 8821. Blood. 1999;94:3707–16.
4. Forestier E, Izraeli S, Beverloo B, Haas O, Pession A, Michalova K, et al. Cytogenetic features of acute lymphoblastic and myeloid leukemias in pediatric patients with Down syndrome: an iBFM-SG study. Blood. 2008;111:1575–83.
5. Hama A, Muramatsu H, Makishima H, Sugimoto Y, Szpurka H, Jasek M, et al. Molecular lesions in childhood and adult acute megakaryoblastic leukaemia. Br J Haematol. 2012;156:316–25.
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