# The Role of BCL2 Mediated Calcium Signaling in Leukemia Stem Cell Metabolism

> **NIH NIH F30** · UNIVERSITY OF COLORADO DENVER · 2022 · $51,752

## Abstract

PROJECT SUMMARY
 The objective of this study is to define the molecular mechanisms that control survival of malignant stem
cells in acute myeloid leukemia (AML). Acute myeloid leukemia (AML) is a hematologic malignancy characterized
by poorly differentiated hematopoietic stem cells (25). Traditionally, outcomes have been poor with a 30%
response rate to standard of care in patients 65 years and older (25,26). A large cause of resistance and relapse
to therapy is the persistence of leukemia stem cells (LSCs) (27-30). LSCs are a population of self-renewing cells
that are able to initiate and maintain disease in immune-compromised animals (27). Traditional chemotherapy
agents do not efficiently eradicate LSCs, and development of more effective therapies is a significant unmet
need (27-30).
 Previous work from the Jordan lab has shown that LSCs have a unique dependence on oxidative
phosphorylation (OXPHOS) for energy production (1-3,24). Further, BCL2 has a non-canonical role in regulating
LSC metabolism as inhibition of BCL2 led to decreased OXPHOS and subsequent cell death in primary human
LSCs (1-3,24). Analysis of samples from AML patients treated with the BCL2 inhibitor drug venetoclax revealed
direct targeting of LSCs, which correlated with a 70% response rate (3). Thus, the underlying premise of the
current proposal is that BCL2-mediated control of OXPHOS represents a key vulnerability that can be exploited
to selectively target LSCs. Further, determining how OXPHOS is inhibited through BCL2 has implications for
improving therapeutic strategies for AML patients.
 This proposal aims to elucidate the mechanistic link between BCL2 and LSC OXPHOS. In several model
systems, BCL2 has been shown to have a non-canonical function in influencing calcium uptake and release at
the ER and mitochondria through direct interactions with membrane bound calcium channels (7). Intracellular
calcium homeostasis is crucial for cell survival, signaling and metabolism. In particular, the three rate limiting
enzymes of the TCA cycle, pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase and isocitrate
dehydrogenase are calcium dependent reactions (7). Therefore, BCL2 mediated calcium movement between
the ER and mitochondria could be a mechanistic link between BCL2 and OXPHOS activity. BCL2 modulates the
activity of calcium channels at the ER and mitochondria differently, based on the cell type being studied (7).
Therefore, my proposal is focused on determining how BCL2 modulates OXPHOS activity by regulating calcium
channel biology in leukemia stem cells. My hypothesis is that BCL2 mediated calcium localization is a
critical regulator of OXPHOS activity in leukemia stem cells. This proposal will determine whether 1) BCL2
mediates calcium channel biology in LSCs 2) calcium channel biology modulates LSC metabolism/function and
3) regulation of calcium localization is the mechanism of action of BCL2 inhibition in LSCs.

## Key facts

- **NIH application ID:** 10425260
- **Project number:** 5F30CA254251-02
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Anagha Inguva
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $51,752
- **Award type:** 5
- **Project period:** 2021-07-01 → 2023-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10425260

## Citation

> US National Institutes of Health, RePORTER application 10425260, The Role of BCL2 Mediated Calcium Signaling in Leukemia Stem Cell Metabolism (5F30CA254251-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10425260. Licensed CC0.

---

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