AKAP95 condensates regulate transcription and can be targeted in MLL-fusion driven oncogenesis.

RNA binding proteins could regulate transcription through modulating RNA polymerase II involved transcriptional condensates with the aid of nascent RNA. However, whether this mechanism also contributes to tumorigenesis is still unknown. Here, we show the RBP AKAP95 is required for MLL rearranged leukemogenesis. Phase separation and RNA binding properties of AKAP95 modulate Pol II recruitment into condensates at genome-wide target sites. AKAP95 interact with MLL1 translocated fragment and their partial co-condensation leads to stronger AKAP95 binding towards MLL-AF9 target genes. Loss of AKAP95 significantly downregulates expression of MLL-AF9 targets and impairs MLL-AF9 driven leukemogenesis. AKAP95 is not essential for normal and regenerative hematopoiesis, rendering it an ideal target for leukemia therapeutics. As an endeavor for modifying condensates, we design a peptide JD-PI95 bridging AKAP95 to protein quality surveillance component HSP70. The peptide successfully impairs AKAP95 phase separation, attenuates gene transcription and inhibits MLLr leukemia cells proliferation. Our work demonstrates an important role of RBP condensates in tumorigenesis through regulation of transcription and a new method to perturb specific condensates for tumor inhibition.