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Single-Cell Dissection of Cellular and Transcriptional Dynamics Driving Post-Transplant Relapse in Myelodysplastic Syndromes

Award Number: R03HL185154
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2026
PERIOD OF PERFORMANCE END DATE: 06/30/2028

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Single-Cell Dissection of Cellular and Transcriptional Dynamics Driving Post-Transplant Relapse in Myelodysplastic Syndromes - ABSTRACT Allogeneic hematopoietic cell transplantation (allo-HCT) remains the only curative therapy for myelodysplastic syndromes (MDS), a heterogenous group of clonal hematopoietic stem cell disorders. Its curative potential is primarily attributed to the graft-versus-leukemia (GVL) effect, mediated by donor T cells. However, disease relapse after allo-HCT continues to be a major clinical challenge and the leading cause of HCT failure. Multiple lines of evidence – including preliminary data from the PI’s K01 award – indicate that both genomic and non- genomic factors contribute to immune escape and posttransplant relapse. Despite these insights, the transcriptional programs orchestrated by these mechanisms remain poorly understood. To elucidate the molecular drivers of relapse, the proposed study will leverage longitudinal samples from 20 MDS patients enrolled in the Bone Marrow Transplant Clinical Trials Network Study #1203. Using paired single-cell RNA sequencing (scRNA-seq) and T cell receptor (TCR) sequencing (scTCR-seq), along with targeted gene sequencing of MDS-associated somatic mutations, we aim to map the dynamic immune landscape following allo-HCT. The study cohort will be comprised of 10 MDS patients who relapsed within one-year post-HCT (cases) and 10 patients who remained relapse-free for at least one year (controls). Peripheral blood mononuclear cells (PBMCs) were collected longitudinally at days 35, 100, 180, and 365 post-HCT. Paired scRNA-seq and scTCR- seq will be performed on all available PBMC samples from controls and on pre-relapse samples from cases. We will profile the single-cell landscape and temporal dynamics of T cells and TCR repertoires at each time point and assess how pre-HCT treatment regimens and donor type influence post-HCT T cell composition, functional states, and TCR clonality (Aim 1). Deep targeted sequencing of 31 MDS-associated genes included in the molecular prognostic model (IPSS-Molecular) will be performed on preconditioning samples to identify MDS- associated somatic mutations that can serve as markers of measurable residual disease (MRD). We will identify T cell subsets and functional states that contribute to relapse after allo-HCT and evaluate how the presence of specific mutations or MRD status influences donor T cell phenotypes, functional states, and clonal architecture (Aim 2). This study will generate preliminary data to identify T cell phenotypes, clonal dynamics, and gene signatures associated with posttransplant relapse, while also examining their interplay with MDS-associated somatic mutations. By integrating high-resolution single-cell and genomic approaches, this R03 project represents a focused and innovative extension of the PI’s ongoing K01 research. It leverages institutional resources and prior insights to advance mechanistic understanding of relapse biology, while supporting the PI’s trajectory toward becoming an independent investigator committed to precision medicine approaches for relapse prediction and prevention in MDS.


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 = $234,000 )
2026	2026	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Blood Diseases and Resources Research	000	1	6/30/2026	NEW	$234,000
														Subtotal = $234,000

Grand Total All Awards = $234,000

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Single-Cell Dissection of Cellular and Transcriptional Dynamics Driving Post-Transplant Relapse in Myelodysplastic Syndromes

Award Number: R03HL185154

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/01/2026

PERIOD OF PERFORMANCE END DATE: 06/30/2028

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