# Selective Radionuclide Delivery for Precise Bone Marrow Niche Alterations

> **NIH NIH R21** · FRED HUTCHINSON CANCER CENTER · 2024 · $89,172

## Abstract

PROJECT SUMMARY / ABSTRACT
The bone marrow niche houses hematopoietic stem cells (HSCs), cells that self-renew and differentiate into vital
blood components like white blood cells, red blood cells, and platelets. HSCs are supported by other marrow
resident cells, like vascular endothelial cells and stromal cells, that nourish the marrow with essential signals.
Unfortunately, radiation and/or chemotherapy used to treat cancer patients injure the bone marrow niche.
Damaged bone marrow function places patients at potentially fatal risks from low blood counts. Because blood
cancers are exquisitely sensitive to radiation, targeted radiation delivery via radioimmunotherapy, or target-
specific antibodies stably linked to radioactive isotopes, has been developed to treat hematologic malignancies,
though some have with slow bone marrow recovery. Despite increasing clinical trials evaluating
radioimmunotherapies, how these delivered radionuclides impact the cellular, molecular, and systemic
mechanisms that regulate the bone marrow niche has yet to be identified. The impact of radioimmunotherapy
on the bone marrow niche must be addressed if radioimmunotherapies are to gain traction, and specifics on
these mechanisms can be leveraged to minimize radiation-induced marrow toxicity. Further complicating the
utility of radioimmunotherapy, radionuclides have distinct payload characteristics with unknown consequences
on the bone marrow niche. This proposal will uncover the differential effects of an alpha-emitter (astatine-211)
and a beta-emitter (yttrium-90) compared to non-targeted X-ray radiation to procure essential knowledge to
advance these technologies clinically. We will report how these radiation types differentially regulate the
abundance and function of HSCs, endothelial and stromal cells, essential regulators of hematologic function. We
will also compare how radiation targeting impacts bone marrow components by comparing how
radioimmunotherapy using a broad hematologic marker (CD45) and more restricted surface marker (CD33)
impacts bone marrow components. Experimentally, we will use in vivo competitive transplantation assays in mice
to assess long-term and short-term HSC potential as a function of radioimmunotherapy. These studies will be
coupled with flow cytometry to quantify how radiation type regulates hematopoietic, vascular, and stromal cell
frequency, death, and proliferation. We will leverage cutting-edge confocal imaging with thick femur sections to
understand how radioimmunotherapy differentially regulates the three-dimensional bone marrow architecture,
critical for vascular niche function and hematologic recovery from irradiation. More importantly, differential gene
expression in the HSC, endothelial and stromal cell compartments, as a response to differential radionuclide
delivery, will also be quantified using RNA sequence analyses. The results from these experiments stand to
identify mechanisms responsible for radiation injury in HSCs, a...

## Key facts

- **NIH application ID:** 11043516
- **Project number:** 3R21CA283589-02S1
- **Recipient organization:** FRED HUTCHINSON CANCER CENTER
- **Principal Investigator:** Johnnie Jose Orozco
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $89,172
- **Award type:** 3
- **Project period:** 2023-07-05 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11043516

## Citation

> US National Institutes of Health, RePORTER application 11043516, Selective Radionuclide Delivery for Precise Bone Marrow Niche Alterations (3R21CA283589-02S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11043516. Licensed CC0.

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