Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2016 Sep;30(9):1816-23.
doi: 10.1038/leu.2016.164. Epub 2016 Jun 10.

The biology, pathogenesis and clinical aspects of acute lymphoblastic leukemia in children with Down syndrome

P Lee  1 , R Bhansali  2 , S Izraeli  3 , N Hijiya  1   4 , J D Crispino  2
Affiliations
Review

The biology, pathogenesis and clinical aspects of acute lymphoblastic leukemia in children with Down syndrome

P Lee et al. Leukemia. 2016 Sep.

Abstract

Children with Down syndrome (DS) are at a 20-fold increased risk for acute lymphoblastic leukemia (DS-ALL). Although the etiology of this higher risk of developing leukemia remains largely unclear, the recent identification of CRLF2 (cytokine receptor like factor 2) and JAK2 mutations and study of the effect of trisomy of Hmgn1 and Dyrk1a (dual-specificity tyrosine phosphorylation-regulated kinase 1A) on B-cell development have shed significant new light on the disease process. Here we focus on the clinical features, biology and genetics of ALL in children with DS. We review the unique characteristics of DS-ALL on both the clinical and molecular levels and discuss the differences in treatments and outcomes in ALL in children with DS compared with those without DS. The identification of new biological insights is expected to pave the way for novel targeted therapies.

PubMed Disclaimer

Conflict of interest statement

Conflicts of Interest: Dr. Hijiya is a consultant for Novartis. The other authors report no conflicts of interest.

Figures

Figure 1
Figure 1. Schematic of genetic events implicated in the etiology of DS-ALL
Several genetic events cooperate in the pathogenesis of DS-ALL, with trisomy 21 being an underlying factor. While overexpression of CRLF2 (A) or JAK2 activating mutations (B) alone are not sufficient to induce cytokine-independent growth, the combination of the two genetic aberrations can induce constitutive JAK-STAT signaling and promote leukemia (C). Recent evidence has indicated that NRAS and KRAS mutations (D) occur in some cases and are mutually exclusive with JAK2 mutations, indicating that other signaling components can promote proliferation downstream of CRLF2 mutations and other inciting events. Similarly, it has also been found that gain-of-function IL7R mutations (E) allow for dimerization with CRLF2 and cytokine-independent growth, which is further enhanced in the presence of TSLP (denoted by bolded line). However, despite of the prevalence of these driver mutations, many cases of DS-ALL occur without this combination of events. Recent evidence suggests contributions of trisomy of HMGN1 and DYRK1A and deletions of PAX5 and IKZF (F). Of note, the latter two events were needed in combination with CRLF2 overexpression and a JAK2 activating mutation for development of an animal model of DS-ALL (35). These genetic alterations exhibit an enormous variability in both nature and frequency, underscoring the complexity behind the pathogenesis of DS-ALL.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Seewald L, Taub JW, Maloney KW, McCabe ER. Acute leukemias in children with Down syndrome. Molecular Genetics & Metabolism. 2012;107(1-2):25–30. - PubMed
    1. Ross JA, Spector LG, Robison LL, Olshan AF. Epidemiology of leukemia in children with Down syndrome. Pediatr Blood Cancer. 2005;44(1):8–12. - PubMed
    1. Vis JC, Duffels MG, Winter MM, Weijerman ME, Cobben JM, Huisman SA, et al. Down syndrome: a cardiovascular perspective. Journal of Intellectual Disability Research. 2009;53(5):419–25. - PubMed
    1. Watt T, Robertson K, Jacobs RJ. Refractive error, binocular vision and accommodation of children with Down syndrome. Clin Exp Optom. 2015;98(1):3–11. - PubMed
    1. Ferreira-Vasques AT, Lamônica DA. Motor, linguistic, personal and social aspects of children with Down syndrome. Journal of Applied Oral Science. 2015;23:424–30. - PMC - PubMed

Publication types

MeSH terms