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

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.

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.