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

Area of Science:

• Molecular Biology
• Cancer Biology
• Transcriptional Regulation

Background:

• RNA binding proteins (RBPs) can regulate transcription via RNA polymerase II-dependent transcriptional condensates.
• The role of RBPs in tumorigenesis, particularly in leukemogenesis, remains largely unexplored.

Purpose of the Study:

• To investigate the role of the RBP AKAP95 in MLL-rearranged leukemogenesis.
• To explore the mechanism by which AKAP95 regulates transcription and condensate formation in leukemia.
• To develop a therapeutic strategy targeting RBP condensates in leukemia.

Main Methods:

• Investigated AKAP95's role in MLL-rearranged leukemogenesis using molecular and cellular assays.
• Analyzed phase separation and RNA binding properties of AKAP95.
• Studied the interaction between AKAP95 and MLL1 translocated fragments.
• Designed and tested a peptide (JD-PI95) to disrupt AKAP95 condensates.

Main Results:

• AKAP95 is essential for MLL-rearranged leukemogenesis, modulating Pol II recruitment into condensates at target sites.
• AKAP95 interacts with MLL1 fragments, enhancing binding to MLL-AF9 target genes and driving leukemogenesis.
• Loss of AKAP95 downregulates MLL-AF9 targets and impairs leukemia development, while normal hematopoiesis remains unaffected.
• The designed peptide JD-PI95 successfully disrupted AKAP95 condensates, attenuated gene transcription, and inhibited leukemia cell proliferation.

Conclusions:

• AKAP95 plays a critical role in MLL-rearranged leukemogenesis through RBP condensates and transcriptional regulation.
• AKAP95 is a potential therapeutic target for leukemia due to its non-essential role in normal hematopoiesis.
• Perturbing specific RBP condensates offers a novel strategy for cancer therapy.