# Leukemia stem cell polarity and differentiation therapy

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2020 · $442,805

## Abstract

Abstract:
Over half of all patients with acute myeloid leukemia (AML) succumb to refractory or relapsed
disease due to a failure to eradicate the leukemia initiating cells (LICs) at the root of leukemia
emergence and propagation. LICs are characterized by acquired capacity for self-renewal and
dormancy contributing to chemotherapy resistance. These attributes are conferred by both
intrinsic, oncogene-driven factors, as well as signals from interactions with extracellular matrix
and soluble factors within a supportive niche in the bone marrow (BM). Preventing the
undesired self-renewal potential and promoting a differentiation program in LICs will have
therapeutic benefits; however, our rudimentary understanding of the mechanism controlling LIC
residency in the niche and its self-renewal regulation limits translation of such a concept to the
clinic. A lesson from the regulatory mechanism of hematopoietic stem cells (HSCs) provides
useful clues: one model suggests that the type of stem cell division (symmetric vs. asymmetric)
determines the cell fate of the resulting daughter cells, with symmetric division resulting in
daughter cells with similar regenerative potential and asymmetric division leading to daughter
cells with dissimilar fates. Based on our extensive preliminary data and the literature, we
propose a novel hypothesis that LIC polarity regulated by intracellular Cdc42 activity affects the
LIC cell division symmetry and consequently the self-renewal/differentiation potential. By using
an array of highly innovative and multi-disciplinary approaches combining the strength and
expertise of the co-principal investigators, we will determine the relationship of Cdc42 regulated
cell polarity and division symmetry in LIC self-renewal and differentiation. A potentially causal
role of Cdc42 activity in coordinating LIC polarity, division symmetry and differentiation will be
established. We will further delineate the Cdc42-mediated signaling pathways that regulate LIC
polarity and mode of division, and begin a preclinical testing of the novel strategy of targeting
Cdc42 in human AML as a differentiation therapy in mouse xenograft models. The studies will
use state of the art animal models, imaging, chemical biology, mouse genetics, and stem cell
methodologies like single cell transplants combined with patient derived leukemia samples to
define the molecular basis of cell polarity and divisional symmetry and their causal role in
determining LIC cell fate.

## Key facts

- **NIH application ID:** 9971478
- **Project number:** 5R01CA204895-04
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** JAMES C MULLOY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $442,805
- **Award type:** 5
- **Project period:** 2017-09-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9971478

## Citation

> US National Institutes of Health, RePORTER application 9971478, Leukemia stem cell polarity and differentiation therapy (5R01CA204895-04). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9971478. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*