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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE271858 | GEO | 2025/11/11

REPOSITORIES: GEO

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AKAP95 condensates regulate transcription and can be targeted in MLL-fusion driven oncogenesis (PRO-Seq)

Project description:Oncogenic transcription represents a crucial event in MLL rearranged (MLLr) leukemia, yet the precise role of transcription co-activators in MLL-fusion protein-associated transcription and their contribution to leukemogenesis remain incompletely understood. Here, we demonstrate that AKAP95 is notably up-regulated in both MLLr patients and in MLL-AF9-transformed mouse bone marrow. AKAP95 proves essential for initiating mouse MLL-AF9 leukemia, exhibiting widespread DNA binding across the genome, particularly at gene promoters. Interaction with the translocated MLL1 fragment primarily occurs through phase separation mechanisms. AKAP95's RNA-binding properties, coupled with its phase separation behavior, govern its binding to pre-mRNA and concurrent transcriptional regulation. Importantly, we engineered a peptide to disrupt its phase separation, effectively attenuating AKAP95-mediated transcriptional co-activation and inhibiting the growth of MLLr cell lines. These findings illustrate a vivid example of an RNA-binding protein orchestrating transcription and tumorigenesis via phase separation, underscoring the potential for targeting oncogenic condensation mechanisms therapeutically.

2025-11-11 | GSE271856 | GEO

AKAP95 condensates regulate transcription and can be targeted in MLL-fusion driven oncogenesis (CLIP-Seq)

2025-11-11 | GSE271855 | GEO

AKAP95 condensates regulate transcription and can be targeted in MLL-fusion driven oncogenesis (ChIP-Seq)

2025-11-11 | GSE271854 | GEO

AKAP95 condensates regulate transcription and can be targeted in MLL-fusion driven oncogenesis (RNA-Seq)

2025-11-11 | GSE271857 | GEO

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

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

| PRJNA1133755 | ENA

AKAP95 condensates regulate transcription and can be targeted in MLL-fusion driven oncogenesis (PRO-Seq)

Project description:AKAP95 condensates regulate transcription and can be targeted in MLL-fusion driven oncogenesis (PRO-Seq)

| PRJNA1133761 | ENA

AKAP95 condensates regulate transcription and can be targeted in MLL-fusion driven oncogenesis (RNA-Seq)

Project description:AKAP95 condensates regulate transcription and can be targeted in MLL-fusion driven oncogenesis (RNA-Seq)

| PRJNA1133760 | ENA

AKAP95 condensates regulate transcription and can be targeted in MLL-fusion driven oncogenesis (CLIP-Seq)

Project description:AKAP95 condensates regulate transcription and can be targeted in MLL-fusion driven oncogenesis (CLIP-Seq)

| PRJNA1133758 | ENA

AKAP95 condensates regulate transcription and can be targeted in MLL-fusion driven oncogenesis (ChIP-Seq)

Project description:AKAP95 condensates regulate transcription and can be targeted in MLL-fusion driven oncogenesis (ChIP-Seq)

| PRJNA1133759 | ENA

Biophysical properties of AKAP95 protein condensates regulate splicing and tumorigenesis.

Project description:It remains unknown if biophysical or material properties of biomolecular condensates regulate cancer. Here we show that AKAP95, a nuclear protein that regulates transcription and RNA splicing, plays an important role in tumorigenesis by supporting cancer cell growth and suppressing oncogene-induced senescence. AKAP95 forms phase-separated and liquid-like condensates in vitro and in nucleus. Mutations of key residues to different amino acids perturb AKAP95 condensation in opposite directions. Importantly, the activity of AKAP95 in splice regulation is abolished by disruption of condensation, significantly impaired by hardening of condensates, and regained by substituting its condensation-mediating region with other condensation-mediating regions from irrelevant proteins. Moreover, the abilities of AKAP95 in regulating gene expression and supporting tumorigenesis require AKAP95 to form condensates with proper liquidity and dynamicity. These results link phase separation to tumorigenesis and uncover an important role of appropriate biophysical properties of protein condensates in gene regulation and cancer.

| S-EPMC7425812 | biostudies-literature

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