13q12.2 deletions and FLT3 overexpression in acute leucemias

Abstract

It was with great enthusiasm that we read the recently published work by Yang and colleagues entitled “13q12.2 deletions in acute lymphoblastic leukemia lead to upregulation of FLT3 through enhancer hijacking.” 1 In their very well-conducted study, the authors show a novel mechanism of FLT3 disruption in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). In 2019, we had anticipated that unknown mechanisms were to be discovered in acute leukemias with FLT3 overexpression.2 With this in mind, we highlighted that a substantial proportion of either BCP-ALL, T-cell acute lymphoblastic leukemia (T-ALL), or acute myeloid leukemia (AML) cases with FLT3 overexpression lacked a known mechanism leading to this upregulation. Yang et al described in their article that somatic 13q12.2 deletions were present in approximately 2% of all BCP-ALL cases included in the study (5 different cohorts have been evaluated), and they discovered that these deletions lead to high expression levels of FLT3 through chromatin remodeling and enhancer hijacking. In brief, the 13q12.2 microdeletion results in cis interactions between the FLT3 promoter and an enhancer element in intron 8 of PAN3, which ultimately leads to FLT3 upregulation. Although a population-based cohort study is still needed to define the actual frequency of these deletions in BCP-ALL, it is important to note that Yang and colleagues also reported that the 13q12.2 deletions are more frequent in high hyperdiploid BCP-ALL cases. However, other acute leukemia subtypes have not yet been evaluated