IGF2BP3 is a key regulator for the abundance of t(4;11) fusion mRNA and protein

The chromosomal translocation t(4;11)(q21;q23) is the most frequently diagnosed genetic aberration in KMT2A-r acute leukemia patients. Although we understand the molecular functions of both wildtype KMT2A and AFF1 multiprotein complexes, little is known about the interplay between the fusion proteins KMT2A::AFF1 (MA4) and AFF1::KMT2A (A4M). Here, we established model systems to investigate their interplay and the role of RNA binding proteins IGF2BP1-3. In addition, we compared the murinized version KMT2A::mAff1 (MmA4) with the full human KMT2A::AFF1 fusion protein to understand the differences between the artificial and the real fusion protein. Our data suggest that A4M ameliorates the negative impact of MA4 expression, due to the fact that only few target genes are extremely high expressed. The protein abundance of MA4 is negatively controlled by IGF2BP3, while IGF2BP3 increases A4M. By contrast, MmA4 does not appear to be controlled by the IGF2BP proteins. Since A4M exerts chromatin-opening activities, it increases the number of potential target genes for MA4 which is accompanied by a much lower ratio of transcripts per target gene. Subsequently, a positive selection process enables MA4 to establish leukemogenic gene signatures, and thus, allows the conversion of a healthy HPSC into a leukemic stem cell.