# (PQ5) Mitochondria in Leukemic Stem Cell Disease Progression

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2020 · $386,619

## Abstract

ABSTRACT
 Conventional and targeted therapies have had little success in eradicating myeloid malignancies
including in myeloproliferative neoplasms (MPNs). The inability to reliably prevent the generation of a small
subset of drug-resistant stem cell-like leukemic cells (or leukemic stem cells (LSCs)) that cause relapse and
the incapacity to target LSC has contributed to this failure. Mitochondrial metabolism has been implicated in
regulating both LSC and hematopoietic stem cells (HSC) activity, however many other aspects of
mitochondrial functions that contribute to the health of stem cell machinery remain largely unknown. We
have discovered mitochondrial heterogeneity in a highly purified population of primitive HSC. Overall our
results indicate that mitochondrial heterogeneity might subdivide stem cell compartment into fractions with
distinct properties and activities. In addition, we have shown that the transcription factor FOXO3 that is
required for both normal hematopoietic and leukemic stem cell maintenance is essential for HSC
mitochondrial metabolism. Based on our studies and the similarities of normal blood-forming and leukemic
stem cells, we propose to test the hypothesis that deregulated FOXO3 activity promotes the generation of
pre-leukemic stem cells in the context of myeloid malignancies. We propose to test this hypothesis in a
model of MPN that designate a group of blood clonal stem cell disorders that have the potential to progress
to leukemia and in which metabolic/mitochondrial pathways have been broadly implicated. We will take
advantage of mitochondrial heterogeneity to identify subpopulations of HSC and LSC with distinct stem cell
properties and potential. Aim 1: To investigate functional consequences of Long-term-HSC
mitochondrial heterogeneity; Aim 2: To elucidate the mechanism of FOXO3 regulation of
mitochondria in stem cells. These studies are highly likely to improve our understanding of leukemic stem
cell biology and the contribution of mitochondria to the LSC generation.

## Key facts

- **NIH application ID:** 9984323
- **Project number:** 5R01CA205975-05
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** SAGHI GHAFFARI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $386,619
- **Award type:** 5
- **Project period:** 2016-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9984323

## Citation

> US National Institutes of Health, RePORTER application 9984323, (PQ5) Mitochondria in Leukemic Stem Cell Disease Progression (5R01CA205975-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9984323. Licensed CC0.

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