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Understanding of mutant splicing factor-derived novel protein isoforms in clonal hematopoietic disorders and antigen presentation.

Award Number: K99CA314714
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 07/03/2026
PERIOD OF PERFORMANCE END DATE: 06/30/2028

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Understanding of mutant splicing factor-derived novel protein isoforms in clonal hematopoietic disorders and antigen presentation. - Somatic mutations in the RNA splicing factor genes U2AF1, SF3B1, and SRSF2 are the most common class of genetic alterations in patients with myelodysplastic syndromes (MDS) and also occur in the MDS precursor conditions, clonal hematopoiesis (CH) and clonal cytopenias of undetermined significance (CCUS). Despite their prevalence, the mechanisms by which these mutations drive disease development are not yet clear. Splicing factor mutations alter RNA binding and splicing specificity, generating aberrant RNA isoforms, including previously unannotated transcripts that escape non-sense mediated decay (NMD) and encode novel proteins. These NMD-neutral isoforms represent an underexplored class of functional variants that may drive clonal dominance. To identify disease relevant isoforms created by splicing factor mutations in a highthroughput manner, we developed a DNA-barcoded open reading frame (ORF) library encoding wild-type and mis-spliced transcripts, and performed in vivo cDNA screens in murine hematopoietic progenitors. These studies revealed multiple novel isoforms that drive MDS disease development in vivo. One of the strongest hits was a mutant U2AF1-derived mis-spliced isoform of SPPL2A (Signal Peptide Peptidase-Like 2A), an intramembrane protease that regulates MHC class II antigen processing in antigen-presenting cells (APCs). We found that this SPPL2A isoform retains the ORF but harbors a disrupted catalytic domain, impairs MHC class II surface localization, and drives myeloid expansion and anemia in vivo, particularly in cooperation with loss of the tumor suppressor, TET2. Here we hypothesize that NMD-insensitive, mis-spliced isoforms induced by splicing factor mutations contribute to MDS development through both cell-intrinsic and immune-modulatory mechanisms. More specifically, we hypothesize that mis-splicing of SPPL2A induced by U2AF1 mutations impairs MHC II antigen presentation and modulates immune-hematopoietic precursor interactions to promote clonal expansion and hematopoietic dysfunction of U2AF1-mutant HSPCs. We will evaluate this hypothesis through biochemical and molecular studies of the impact of SPPL2A isoforms on antigen presentation as well as in vivo (mouse) studies based on alterations in SPPL2A and its downstream pathways. The laboratory mouse (Mus musculus) is scientifically appropriate for this project because it provides an intact hematopoietic and immune system to evaluate how mis-spliced isoforms affect malignant hematopoietic transformation, clonal expansion, and disease-related changes in vivo. These complex biological processes cannot be faithfully replicated using non-animal alternatives such as cell culture, tissue culture, or computational models. In addition, our proposed in vivo studies align with NIH and NCI priorities to advance cancer biology and improve understanding of cancer development and treatment. We will also apply recent methods developed in our lab to track splicing factor mutant cells and antigen specific T cells in patient bone marrow biopsies in situ using spatial transcriptomics. These studies will address a critical gap in understanding how U2AF1 mutations drive premalignant hematopoiesis through generation of mis-spliced protein isoforms and regulation of HSPC– immune interactions. Aim 1 (K99). Determine how mutant U2AF1 alters MHC class II cell surface localization and impairs antigen presentation in hematopoietic cells via mis-spliced SPPL2A isoform. Aim 2 (K99/R00). Define the cell-intrinsic and immune-mediated contributions of the SPPL2A aberrant isoform to hematopoietic clonal expansion and bone marrow failure. Aim 3 (R00). Evaluate interactions between U2AF1 mutant MDS HSPCs in situ and in the bone marrow immune microenvironment.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $137,631 )
2026	2026	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Research Manpower	000	1	7/7/2026	NEW	$137,631
														Subtotal = $137,631

Grand Total All Awards = $137,631

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Understanding of mutant splicing factor-derived novel protein isoforms in clonal hematopoietic disorders and antigen presentation.

Award Number: K99CA314714

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 07/03/2026

PERIOD OF PERFORMANCE END DATE: 06/30/2028

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