Influence of IGF2BP3 on t(4;11) fusion mRNA and protein abundance.

The chromosomal translocation t(4;11)(q21;q23) is the most common genetic aberration in KMT2A-rearranged acute leukemia. Although the molecular functions of wild-type KMT2A and AFF1 complexes are well characterized, little is known about the interplay between the reciprocal fusion proteins KMT2A::AFF1 (MA4) and AFF1::KMT2A (A4M). Here, we established model systems to investigate this interplay and the role of the RNA-binding proteins IGF2BP1-3. We also compared the murinized fusion KMT2A::mAff1 (MmA4) with the authentic human KMT2A::AFF1 fusion. Our data indicate that MA4 alone drives aberrantly high expression of only a few target genes, whereas A4M counteracts this detrimental effect. Under these conditions, MA4 induces genes encoding RNA-binding proteins as a counterregulatory response. Both reciprocal fusion transcripts are bound by IGF2BP3, resulting in reduced MA4 protein abundance but increased A4M levels. This effect was not observed for the artificial MmA4 fusion, likely because it cannot recruit the SL-1 complex. Together with previous findings, our results suggest that A4M is crucial through its chromatin-opening activity, which strongly expands the pool of MA4 target genes and thereby promotes the establishment of pre-leukemogenic and leukemogenic gene expression programs.