Insights into the Manifestations, Outcomes, and Mechanisms of Leukemogenesis in Down Syndrome

Overview

Journal Blood

Publisher Elsevier

Specialty Hematology

Date 2009 Jan 14

PMID 19139078

Citations 95

Authors

Sebastien Malinge

Shai Izraeli

John D Crispino

Affiliations

Soon will be listed here.

Abstract

Children with Down syndrome (DS) show a spectrum of clinical anomalies, including cognitive impairment, cardiac malformations, and craniofacial dysmorphy. Moreover, hematologists have also noted that these children commonly show macrocytosis, abnormal platelet counts, and an increased incidence of transient myeloproliferative disease (TMD), acute megakaryocytic leukemia (AMKL), and acute lymphoid leukemia (ALL). In this review, we summarize the clinical manifestations and characteristics of these leukemias, provide an update on therapeutic strategies and patient outcomes, and discuss the most recent advances in DS-leukemia research. With the increased knowledge of the way in which trisomy 21 affects hematopoiesis and the specific genetic mutations that are found in DS-associated leukemias, we are well on our way toward designing improved strategies for treating both myeloid and lymphoid malignancies in this high-risk population.

Citing Articles

Down syndrome-associated leukaemias: current evidence and challenges.

Mason N, Cahill H, Diamond Y, McCleary K, Kotecha R, Marshall G Ther Adv Hematol. 2024; 15:20406207241257901.

PMID: 39050114 PMC: 11268035. DOI: 10.1177/20406207241257901.

Paediatric syndromic scoliosis: proceedings of the half-day course at the 57th annual meeting of the Scoliosis Research Society.

Mehta J, Pahys J, Saad A, Sponseller P, Andras L, Marks D Spine Deform. 2024; 12(3):523-543.

PMID: 38366266 DOI: 10.1007/s43390-024-00822-1.

Neurocognitive and psychosocial outcomes in survivors of childhood leukemia with Down syndrome.

Gandy K, Hall L, Krull K, Esbensen A, Rubnitz J, Jacola L Cancer Med. 2024; 13(3):e6842.

PMID: 38240104 PMC: 10905531. DOI: 10.1002/cam4.6842.

The NCOR-HDAC3 co-repressive complex modulates the leukemogenic potential of the transcription factor ERG.

Kugler E, Madiwale S, Yong D, Thoms J, Birger Y, Sykes D Nat Commun. 2023; 14(1):5871.

PMID: 37735473 PMC: 10514085. DOI: 10.1038/s41467-023-41067-2.

Gain of chromosome 21 increases the propensity for acute lymphoblastic leukemia increased expression.

Page E, Heatley S, Rehn J, Thomas P, Yeung D, White D Front Oncol. 2023; 13:1177871.

PMID: 37483494 PMC: 10358767. DOI: 10.3389/fonc.2023.1177871.

References

Hasle H . Pattern of malignant disorders in individuals with Down's syndrome. Lancet Oncol. 2002; 2(7):429-36. DOI: 10.1016/S1470-2045(00)00435-6. View

Malkin D, Brown E, Zipursky A . The role of p53 in megakaryocyte differentiation and the megakaryocytic leukemias of Down syndrome. Cancer Genet Cytogenet. 2000; 116(1):1-5. DOI: 10.1016/s0165-4608(99)00072-2. View

Kirsammer G, Jilani S, Liu H, Davis E, Gurbuxani S, Le Beau M . Highly penetrant myeloproliferative disease in the Ts65Dn mouse model of Down syndrome. Blood. 2007; 111(2):767-75. PMC: 2200841. DOI: 10.1182/blood-2007-04-085670. View

Levanon D, Groner Y . Structure and regulated expression of mammalian RUNX genes. Oncogene. 2004; 23(24):4211-9. DOI: 10.1038/sj.onc.1207670. View

Reeves R, Irving N, Moran T, WOHN A, Kitt C, Sisodia S . A mouse model for Down syndrome exhibits learning and behaviour deficits. Nat Genet. 1995; 11(2):177-84. DOI: 10.1038/ng1095-177. View

Pine S, Guo Q, Yin C, Jayabose S, Druschel C, Sandoval C . Incidence and clinical implications of GATA1 mutations in newborns with Down syndrome. Blood. 2007; 110(6):2128-31. DOI: 10.1182/blood-2007-01-069542. View

Lyle R, Bena F, Gagos S, Gehrig C, Lopez G, Schinzel A . Genotype-phenotype correlations in Down syndrome identified by array CGH in 30 cases of partial trisomy and partial monosomy chromosome 21. Eur J Hum Genet. 2008; 17(4):454-66. PMC: 2986205. DOI: 10.1038/ejhg.2008.214. View

Arico M, Ziino O, Valsecchi M, Cazzaniga G, Baronci C, Messina C . Acute lymphoblastic leukemia and Down syndrome: presenting features and treatment outcome in the experience of the Italian Association of Pediatric Hematology and Oncology (AIEOP). Cancer. 2008; 113(3):515-21. DOI: 10.1002/cncr.23587. View

Dordelmann M, Schrappe M, Reiter A, Zimmermann M, Graf N, Schott G . Down's syndrome in childhood acute lymphoblastic leukemia: clinical characteristics and treatment outcome in four consecutive BFM trials. Berlin-Frankfurt-Münster Group. Leukemia. 1998; 12(5):645-51. DOI: 10.1038/sj.leu.2400989. View

10.

Sato T, Toki T, Kanezaki R, Xu G, Terui K, Kanegane H . Functional analysis of JAK3 mutations in transient myeloproliferative disorder and acute megakaryoblastic leukaemia accompanying Down syndrome. Br J Haematol. 2008; 141(5):681-8. DOI: 10.1111/j.1365-2141.2008.07081.x. View

11.

Creutzig U, Reinhardt D, Diekamp S, Dworzak M, Stary J, Zimmermann M . AML patients with Down syndrome have a high cure rate with AML-BFM therapy with reduced dose intensity. Leukemia. 2005; 19(8):1355-60. DOI: 10.1038/sj.leu.2403814. View

12.

Kuhn D, Nuovo G, Martin M, Malana G, Pleister A, Jiang J . Human chromosome 21-derived miRNAs are overexpressed in down syndrome brains and hearts. Biochem Biophys Res Commun. 2008; 370(3):473-7. PMC: 2585520. DOI: 10.1016/j.bbrc.2008.03.120. View

13.

Herbst E, Winking H . Adoptive transfer of the hematopoietic system of trisomic mice with limited life span: stem cells from six different trisomies are capable of survival. Dev Genet. 1991; 12(6):415-22. DOI: 10.1002/dvg.1020120606. View

14.

Langebrake C, Creutzig U, Reinhardt D . Immunophenotype of Down syndrome acute myeloid leukemia and transient myeloproliferative disease differs significantly from other diseases with morphologically identical or similar blasts. Klin Padiatr. 2005; 217(3):126-34. DOI: 10.1055/s-2005-836510. View

15.

Antonarakis S, Lyle R, Dermitzakis E, Reymond A, Deutsch S . Chromosome 21 and down syndrome: from genomics to pathophysiology. Nat Rev Genet. 2004; 5(10):725-38. DOI: 10.1038/nrg1448. View

16.

Rainis L, Bercovich D, Strehl S, Teigler-Schlegel A, Stark B, Trka J . Mutations in exon 2 of GATA1 are early events in megakaryocytic malignancies associated with trisomy 21. Blood. 2003; 102(3):981-6. DOI: 10.1182/blood-2002-11-3599. View

17.

Carmichael C, Majewski I, Alexander W, Metcalf D, Hilton D, Hewitt C . Hematopoietic defects in the Ts1Cje mouse model of Down syndrome. Blood. 2008; 113(9):1929-37. DOI: 10.1182/blood-2008-06-161422. View

18.

Bourquin J, Subramanian A, Langebrake C, Reinhardt D, Bernard O, Ballerini P . Identification of distinct molecular phenotypes in acute megakaryoblastic leukemia by gene expression profiling. Proc Natl Acad Sci U S A. 2006; 103(9):3339-44. PMC: 1413912. DOI: 10.1073/pnas.0511150103. View

19.

Epstein C, Hofmeister B, Yee D, Smith S, Philip R, Cox D . Stem cell deficiencies and thymic abnormalities in fetal mouse trisomy 16. J Exp Med. 1985; 162(2):695-712. PMC: 2187749. DOI: 10.1084/jem.162.2.695. View

20.

Hama A, Yagasaki H, Takahashi Y, Nishio N, Muramatsu H, Yoshida N . Acute megakaryoblastic leukaemia (AMKL) in children: a comparison of AMKL with and without Down syndrome. Br J Haematol. 2008; 140(5):552-61. DOI: 10.1111/j.1365-2141.2007.06971.x. View