Pathogenesis of ETV6/RUNX1-positive childhood acute lymphoblastic leukemia and mechanisms underlying its relapse

Abstract

ETV6/RUNX1 (E/R) is the most common fusion gene in childhood acute lymphoblastic leukemia (ALL). Multiple lines of evidence imply a "two-hit" model for the molecular pathogenesis of E/R-positive ALL, whereby E/R rearrangement is followed by a series of secondary mutations that trigger overt leukemia. The cellular framework in which E/R arises and the maintenance of a pre-leukemic condition by E/R are fundamental to the mechanism that underlies leukemogenesis. Accordingly, a variety of studies have focused on the relationship between the clones giving rise to the primary and recurrent E/R-positive ALL. We review here the most recent insights into the pathogenic mechanisms underlying E/R-positive ALL, as well as the molecular abnormalities prevailing at relapse.

Keywords: ETV6/RUNX1; childhood acute lymphoblastic leukemia; initiation; mechanisms; relapse.

Figure 1. Two-hit model of the natural history of E/R-positive ALL

Figure 2. Model for pathways influenced by E/R

1) E/R regulates the phosphorylation of STAT3 via activation of RAC1, resulting in the transcriptional induction of MYC. 2) E/R can bind to a principal TGF-β signaling target, Smad3, which has an inhibitory impact on the response to TGF-β signaling. 3) E/R can upregulate MDM2 promoter activity; MDM2 functions as a crucial negative regulator of p53, repressing its activity. 4) E/R activates PI3K/AKT/mTOR signaling and interferes with proliferation, cell adhesion and DNA damage response. Activation of PI3K/AKT/mTOR signaling also promotes the phosphorylation of MDM2 and its localization in the nucleus where it binds to p53. 5) E/R can directly bind the EPOR promoter and increase cell survival through activation of the JAK2-STAT5 pathway and upregulation of antiapoptotic BCL-XL. EPOR is also one of the upstream signaling components of the PI3K/AKT/mTOR signaling cascade. All these signal pathways facilitate the E/R pre-leukemic state.

Figure 3. Models for the relapse of ETV6/RUNX1-positive leukemia

Circles with different gray shades represent E/R (+) clones. Their respective location within the spectrum designates their pre-leukemic or leukemic nature. The relapse clones originate from either a major or minor clone at presentation. A, the relapse CNAs resemble the CNAs at diagnosis, hence the relapse clone derives from the dominant clone at diagnosis. B, the clone at relapse acquires extra CNAs, thus it derives from a derivative minor clone at diagnosis. C, the clone at relapse acquires a completely new set of CNAs, thus it may derive from a minor clone at diagnosis.