Official websites use .gov

A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS

A lock ( 🔒 ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Need Help

The Role of Cell Competition in Shaping the Clonal Structure of Hematopoiesis

Award Number: R01CA317504
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/09/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2031

Group Awards By:

View Award Description

The Role of Cell Competition in Shaping the Clonal Structure of Hematopoiesis - ABSTRACT All humans become genetic mosaics over time as somatic stem cells acquire mutations throughout life. In the hematopoietic compartment, this phenomenon is termed clonal hematopoiesis (CH) when the mutations provide a competitive advantage to those stem cells. The mutations observed in CH overlap with blood diseases. But while the prevalence of CH is universal, risk of disease progression from CH is highly variable. While we know some of the risk factors, one concept that has not been considered in risk prediction models is the influence of the surrounding environment. Human bone marrow becomes a complex genetic milieu with age with CH clones potentially influencing the development of other clones, both in positive and negative ways. Due to the low mutant cell burden in many CH carriers, interaction of clones is difficult to study in humans. But our recent lab studies have indicated that particular clones can support or inhibit other CH mutations depending on the context. One such example is the focus of this proposal. Myeloproliferative neoplasms (MPNs) are chronic hematological diseases driven by mutations acquired in HSCs. In up to 20% of patients, MPN undergoes disease progression which dramatically changes the prognosis for these patients. The classical dogma of disease progression in MPN patients is whereby the MPN clones acquire additional cooperating mutations. But our new singlecell sequencing data from paired patient samples shows the mutations that arise during disease progression can occur in separate clones distinct from the MPN cells. Thus, in such patients the more accurate diagnosis is two separate blood diseases evolving in parallel. Data from our mouse and human model systems show a mechanism of clonal support whereby cytokines secreted by the MPN cells act as an evolutionary pressure that selects for parallel CH clones with TET2 mutations. Here, we will dissect the cell-intrinsic and cell-extrinsic mechanisms that drive these evolutionary processes with the ultimate goal of developing novel interventions to prevent disease progression in MPN patients. This will be accomplished via the following Specific Aims: - Specific Aim 1: Identify characteristics of PV cells that provide selective pressures for TET2-mutant clones. - Specific Aim 2: Develop interventions to mitigate outgrowth of TET2-mutant clones in an MPN background. Disease progression in MPN remains a significant health problem that requires study in pre-clinical models. Mice are used for these in vivo studies because hematopoietic maintenance and evolution can only be studied in the context of an intact animal. We choose to do this work with mouse models because the hematopoietic system of the mouse is very similar to that of humans. We have generated novel mouse strains to recapitulate the genetics of human disease and will complement this with our technical expertise in patient-derived xenografts (PDXs) using primary human specimens in immunodeficient mice to rigorously execute these studies. We will use a combination of singlecell approaches, genetic mouse models and our unique MPN PDX system to study the importance of clonal competition in shaping the clonal structure of hematopoietic development.


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 = $465,749 )
2026	2026	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Biology Research	000	1	9/9/2026	NEW	$465,749
														Subtotal = $465,749

Grand Total All Awards = $465,749

Top

All Categories

About

Search

Reports

Data Submission

Award Information

The Role of Cell Competition in Shaping the Clonal Structure of Hematopoiesis

Award Number: R01CA317504

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/09/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2031

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer