# Clonal and functional analysis of hematopoietic stem cell and progenitor heterogeneity

> **NIH NIH P01** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $419,802

## Abstract

ASBTRACT
Historically, our understanding of the fundamental properties of hematopoietic stem cell (HSC) and
progenitor populations has been largely based on assaying populations of cells. Only recently, single cell
transplantation studies have revealed intrinsic heterogeneity among seemingly pure populations of HSCs.
However, because of the lack of available tools, the existence and mechanistic dissection of functional
heterogeneity in the unperturbed `non-transplanted' marrow has been unfeasible. This is a crucially
important question for the hematology field, as how stem/progenitor clones become activated and how
clone size is controlled are highly relevant for our understanding of normal and malignant hematopoietic
processes. We have recently developed a transposon (Tn)-based system for the simultaneous lineage
tracing of thousands of single cells in the unperturbed bone marrow. With this model, we have
demonstrated that native non-transplant hematopoiesis is highly polyclonal and mainly driven by the action
of cells previously defined as short-term multipotent progenitors (MPPs), and not by the action of long-term
HSCs, as historically thought. Here, in the context of this Program Project, we propose to utilize this system
to examine the clonal response to different types of hematopoietic injury, and identify the consequences of
this response on clonal lifespan and complexity. Our results will be intersected with findings of the Scadden
and Zon groups, performing similar studies using complementary approaches in mice and zebrafish.
Moreover, using a newly developed approach, we aim to define molecular signatures, at the single cell
level, of the heterogeneity in this response. Our data will be analyzed in the context of findings by the Tenen
and Scadden labs, also producing molecular signatures of heterogeneity. Additionally, we will study the
clonal dynamics of blood production during oncogenic stress and determine the effects of pathway-specific
chemical perturbation on the emergence of clonal dominance (Orkin and Zon). Our comprehensive and
integrative studies will shed led on the cellular and molecular mechanisms driving functional heterogeneity
during organismal stress. Moreover, these studies will inform efforts to enhance hematopoietic regeneration
and prevent pre-malignant clonal hematopoiesis.

## Key facts

- **NIH application ID:** 9929650
- **Project number:** 5P01HL131477-04
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Fernando Camargo
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $419,802
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9929650

## Citation

> US National Institutes of Health, RePORTER application 9929650, Clonal and functional analysis of hematopoietic stem cell and progenitor heterogeneity (5P01HL131477-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9929650. Licensed CC0.

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