# Pathologic Signaling Pathways in AML Cells

> **NIH VA I01** · PHILADELPHIA VA MEDICAL CENTER · 2021 · —

## Abstract

Abstract: Acute myeloid leukemia (AML) is a serious blood cancer that affects United
States Veterans and other individuals. Multiple studies have demonstrated that active
signaling pathways are a necessary step to leukemic cell transformation. However, the
mechanism(s) of activated signaling in FLT3 wild type AML are poorly described. We
hypothesize that constitutive activation of the PI3 kinase pathway leads to activation of a
complex called mammalian target of rapamycin 2 (mTORC2) which regulates diverse
pathways to balance cell growth and survival in AML cells. In this proposal, we will
define these signaling pathways and determine if inhibition of mTORC2 alone or in
combination with other drugs will enhance survival in pre-clinical models of AML
leading to new therapies for this challenging disease.
1. Objective(s): The overall objective of the research proposal is to define the
mechanisms of activated cell signaling in AML cells, determine the biochemical
pathways regulated by mTORC2 in AML cells and determine if inhibition of mTORC2
in pre-clinical models can increase survival of individuals with AML.
2. Research Design: We propose three Specific Aims. Specific Aim 1) Confirm that
4EBP1 is a target of MTORC2 and not MTORC1 in human AML samples and define
whether MTORC2 regulates cell survival or cell growth. Specific Aim 2) Determine if
mTORC2 Regulates FOXO 3 phosphorylation in AML cells to Regulate Cell Survival.
Specific Aim 3) Determine if combinatorial MTORC1/MTORC2 inhibition in
combination with chemotherapy or Bcl2 inhibition suppresses AML cell growth in pre-
clinical models.
3. Methodology: Specific Aim 1 will primary use human AML cells and primary
human AML cells in culture. Specific Aim 2 will use similar methods but also assess
FOXO binding to DNA using chromatin immunoprecipitation. Specific Aim 3 will focus
on studies in a xenotransplantation model of AML developed by our laboratory.
4. Findings: We anticipate confirming that mTORC2 is actually a master regulator of
signaling in AML cells. In particular, we anticipate that mTORC2 regulates 4EBP1 to
regulate protein translation. We also anticipate that mTORC2 regulates FOXO proteins to
regulate c-Myc expression. Finally, we anticipate that mTORC2 inhibition will work
alone or in combination with other therapies to inhibit AML cell survival in vivo.
5. Clinical Relationships: These studies will use primary material from patients with
AML and will be used to develop a new approach to therapy of the disease.

## Key facts

- **NIH application ID:** 10010684
- **Project number:** 1I01BX004662-01A1
- **Recipient organization:** PHILADELPHIA VA MEDICAL CENTER
- **Principal Investigator:** MARTIN CARROLL
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2021-01-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10010684

## Citation

> US National Institutes of Health, RePORTER application 10010684, Pathologic Signaling Pathways in AML Cells (1I01BX004662-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10010684. Licensed CC0.

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