# Functional dissection of clonal hematopoiesis

> **NIH NIH P01** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $424,288

## Abstract

Lifelong hematopoiesis involves the proliferation and differentiation of successive clones into mature blood
lineages. Mono- or oligoclonal hematopoiesis can occur in elderly patients who have somatic TET2 or
DNMT3A mutations. The production of blood by one or a few clones with somatic mutations renders patients
susceptible to blood disorders such as refractory cytopenias or myelodysplasia. It is unclear which
combinations of these mutations are sufficient to promote clonal dominance or maintain malignancy. Here, we
have developed a system in the zebrafish to study the genetics of clonality. A Zebrabow fish allows for clonal
labeling of stem cells and their progeny with random combinations of three fluorescent proteins, providing
enough diversity to produce up to 30 detectable colors. Using a tissue-specific inducible CreERT2 system, we
labeled stem cells at 36 hpf of development and then grew the animal to adulthood. This labeled roughly 20
clones of cells, establishing that there are 20 cells of the developing aorta that contributed to adult
hematopoiesis. We have also developed tissue-specific CRISPR technology to target multiple genes
simultaneously. Using this approach, we will look for gene combinations that are required for clonal
hematopoiesis. We then will undertake a chemical screen to find pathways that suppress clonal dominance.
Single cell analysis with the Tenen and Orkin labs will be used to examine specific gene expression in
particular dominant clones after FACS isolation. We plan to evaluate the activity of the genes and small
molecules discovered using the zebrafish in the mouse Hue system (Scadden) and the transposon barcoding
strategy (Camargo). Our collaboration with Dr. Orkin will identify chromatin factors required for the
establishment of normal clonal dynamics. Our studies will have an impact on understanding early clonal
events that regulate normal and malignant hematopoiesis, and could develop novel therapeutics to suppress
clonal hematopoiesis.

## Key facts

- **NIH application ID:** 9929651
- **Project number:** 5P01HL131477-04
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** LEONARD Ira ZON
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $424,288
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9929651

## Citation

> US National Institutes of Health, RePORTER application 9929651, Functional dissection of clonal hematopoiesis (5P01HL131477-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9929651. Licensed CC0.

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