Broad de-regulated U2AF1 splicing is prognostic and augments leukemic transformation via protein arginine...

Area of Science:

• Molecular Biology
• Cancer Research
• Genomics

Background:

• Splicing dysregulation is linked to cancer, often through splicing factor mutations.
• The role of alternative splicing in cancer without these mutations is less understood.
• Acute Myeloid Leukemia (AML) presents an opportunity to study splicing alterations.

Purpose of the Study:

• To develop a novel approach, OncoSplice, for identifying splicing alterations and patient subtypes in AML.
• To investigate the impact of splicing dysregulation independent of known splicing factor mutations.
• To uncover potential therapeutic targets for AML based on splicing mechanisms.

Main Methods:

• Development and application of the OncoSplice computational tool.
• Analysis of splicing patterns in adult and pediatric AML patient cohorts.
• Pharmacological inhibition of PRMT5 and genetic deletion of IRAK4 in preclinical models.
• Assessment of leukemia stem cell (LSC) programs and differentiation induction.

Main Results:

• OncoSplice identified diverse patient subtypes, including a biphasic poor prognosis signature in over 40% of AML cases.
• This signature phenocopies U2AF1-mutant splicing, affecting thousands of genes and co-opting circadian splicing programs.
• Inhibition of PRMT5 corrected aberrant splicing and reduced leukemic cell growth.
• IRAK4 deletion blocked leukemia development and promoted cell differentiation.

Conclusions:

• A novel, mutation-independent splicing mechanism contributes to AML prognosis and progression.
• Targeting specific splicing regulators like PRMT5 and downstream effectors like IRAK4 shows therapeutic potential in AML.
• OncoSplice provides a powerful tool for dissecting complex splicing landscapes in cancer.