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Understanding the spatial and molecular architecture of the bone marrow niche in myelodysplastic syndromes

Award Number: F31CA317812
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 02/13/2027
PERIOD OF PERFORMANCE END DATE: 02/12/2028

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Understanding the spatial and molecular architecture of the bone marrow niche in myelodysplastic syndromes - PROJECT SUMMARY/ABSTRACT Myelodysplastic syndromes (MDS) are clonal hematopoietic disorders characterized by impaired hematopoiesis, dysplastic morphology, and risk of progression to acute leukemia. While much is known regarding genomic alterations intrinsic to MDS disease-initiating cells, molecular assessment of the bone marrow microenvironment in situ has been limited even though evaluation of bone marrow biopsies is essential for MDS diagnosis and management. To this end, we recently generated a large-scale Xenium spatial transcriptomics dataset of bone marrow biopsies from 41 patients with newly diagnosed MDS and 20 control subjects, capturing nearly 6 million single cells. The proposed study builds upon analysis of this preliminary data identifying large aggregates of immune cells with distinct compositions in the bone marrow of MDS patients relative to normal subjects, indicating altered immune response in MDS. Guided by these findings, we hypothesize that malignant clones in MDS remodel the bone marrow microenvironment by driving the formation of immunosuppressive niches that impair T cell function. To address this hypothesis, the proposed project will identify malignant cells in situ (Aim 1) and develop computational methods to profile alterations in local structures associated with MDS (Aim 2). In Aim 1, we will expand our proof-of-concept approach which demonstrates the feasibility of identifying mutations in the RNA splicing factor SF3B1 in situ by designing custom probes to target both mutations and aberrant isoforms associated with mutant SF3B1. As splicing factor mutations are the most frequent class of mutations in MDS, occurring in 50-70% of patients, we will expand our repertoire of targeted mutations to additional mutant splicing factors. Importantly, this identification of mutant cells in situ enables simultaneous spatial and transcriptomic profiling of mutant cells. In Aim 2, a computational method will be developed to identify local structures within the bone marrow microenvironment, enabling the interrogation of niches formed among mutant and immune cells in addition to associated cell signaling activity. Together, the proposed project has the potential to uncover immunosuppressive mechanisms of malignant cells and identify targets for the development of effective immunotherapies for MDS which cannot otherwise be found through the analysis of dissociated cells, conventional histology, or spatial imaging approaches alone.


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 = $50,114 )
2026	2026	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Cancer Research Manpower	000	1	8/13/2026	NEW	$50,114
														Subtotal = $50,114

Grand Total All Awards = $50,114

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Understanding the spatial and molecular architecture of the bone marrow niche in myelodysplastic syndromes

Award Number: F31CA317812

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 02/13/2027

PERIOD OF PERFORMANCE END DATE: 02/12/2028

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