Dataset Information

Targeting RBPMS selectively eliminates leukemia initiating cells via the USP1/m6A/FOXO1 axis

ABSTRACT: Acute myeloid leukemia (AML) is a malignant tumor with high recurrence rate and poor prognosis. RNA-binding proteins (RBPs) are essential modulators of transcription and translation played critical roles and frequently dysregulated in AML. Here we show that RBPMS (RNA binding protein with multiple splicing) which is highly expressed in AML and associated with poor prognosis of AML, plays critical roles in leukemogenesis. Our study shows that inhibition of RBPMS abrogates self-renewal of leukemia initiating cells (LICs) and AML development but has little effect on normal hematopoiesis. Mechanistically, RBPMS maintains the stability of the m6A reader IGF2BP3 by USP1-mediated deubiquitination, which promotes the translation of the FOXO1 mRNA in an m6A-dependent manner. Moreover, RBPMS contributes to the progression of leukemia by promoting FOXO1/ENO2/ALDOC regulated glycolysis. Overexpression of FOXO1 has been shown to rescue RBPMS inhibition-induced phenotypes in both leukemia cells and mouse models. We have also designed a specific inhibitor of RBPMS that has therapeutic effects in the AML patient derived xenograft model (PDX) model. We, therefore, we highlight RBPMS as a promising drug target for AML therapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE230646 | GEO | 2023/10/04

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Background: Modulation of mRNA splicing acts as an important layer of gene regulation, in addition to transcriptional regulation and epigenetic modifications. RNA binding proteins (RBPs) play essential roles in mediating RNA splicing and are key regulators of heart development and function. Our previous studies demonstrated that RBPMS (RNA-binding protein with multiple splicing) regulates cardiac development through modulating mRNA splicing during embryogenesis. Here we explored the postnatal function of RBPMS in the heart. Methods: We ablated Rbpms in the heart by generating a cardiac-specific knockout mouse line (Myh6-Cre, Rbpmsfl/fl), and evaluated its cardiac functions by histology, echocardiography, and gene expression. Paired-end RNA sequencing and RT-PCR were performed to identify and validate splicing targets of RBPMS in adult mouse hearts. Proximity-dependent Biotin Identification (BioID) assay and mass spectrometry analysis were performed to identify RBPMS binding partners. We also measured contractility and calcium fluxes in isolated mouse cardiomyocytes, and contractile forces of cardiac papillary muscle. Human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) were also used as a model to explore the influence of RBPMS on contractility of human cardiomyocytes. Results: he absence of Rbpms in the heart led to dilated cardiomyopathy (DCM) and heart failure, causing early death in mice. Mice with cardiac-specific knockout of Rbpms showed myocardium noncompaction with reduced cardiomyocyte number at the neonatal stage and developed DCM with pervasive myocardial fibrosis in adulthood. We found that RBPMS mediates a largely distinct RNA splicing profile in adult mouse hearts compared to neonatal hearts, indicating a stage-specific modulation of alternative RNA splicing by RBPMS. In adult hearts, RBPMS mainly influenced alternative splicing of genes associated with sarcomere structures and cardiomyocyte contraction, such as Ttn, Pdlim5 and Nexn, to generate new protein isoforms. In neonatal hearts, RBPMS influenced the splicing of cytoskeletal genes. RBMPS was associated with spliceosome factors and other RNA binding proteins that play important roles in the heart, such as RBM20 and GATA4. Importantly, we found that the absence of Rbpms caused severe cardiomyocyte contractile defects and reduced calcium sensitivity in both mouse and hiPSC-CMs. Our results demonstrated that Rbpms is crucial for postnatal cardiac function and cardiomyocyte contractility by regulating RNA alternative splicing. Conclusions: Loss of Rbpms in the heart causes reduced cardiomyocyte number and impaired cardiomyocyte contraction, leading to DCM and heart failure.

Dataset Information

Targeting RBPMS selectively eliminates leukemia initiating cells via the USP1/m6A/FOXO1 axis

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets