# Signaling Pathways and Therapeutic Targeting of Leukemic Cells

> **NIH VA I01** · JESSE BROWN VA MEDICAL CENTER · 2024 · —

## Abstract

This is a competing renewal application of an ongoing merit review program, focused on the mechanisms
of leukemogenesis in acute myeloid leukemia (AML). The program aims to develop innovative new therapeutic
approaches for AML by identifying new cellular targets in leukemic cells. This is of high clinical translational
significance and relevance, as the outcome for most patients with AML remains very poor. Resistance of
leukemia cells continues to be a serious problem and identifying pathways that can be therapeutically targeted
is of high importance. Work from our laboratory has provided evidence for the existence of negative feedback
regulatory loops in AML cells that are engaged in response to antileukemia drugs and mediate leukemic cell
resistance. These include activation of pathways that regulate transcription and mRNA translation of pro-
leukemogenic genes, and other regulatory negative feedback loops.
 In efforts to identify pathways associated with leukemic cell resistance, we discovered that there is
constitutive activation of the ULK1 kinase in AML cells and identified novel phosphorylation sites that may
mediate autophagy-independent activation of downstream effector pathways. Remarkably, we found evidence
for interactions of ULK1 with proteins key in the pathophysiology of AML. These include RUNX1 and other core
binding factor proteins and CHAF1b & CHAF1a. These unexpected findings raise the intriguing hypothesis that
ULK1 directly regulates transcription factors that are important for leukemogenesis and play key roles in the
pathophysiology of AML. The current proposal is a systematic approach to define the mechanisms by which
ULK1 is engaged in leukemogenesis. The proposal aims to use such information towards identifying novel
cellular targets in AML for the development of new therapeutic approaches. Specific aim 1 will define
autophagy independent ULK1 effector pathways and will dissect their roles in leukemogenesis. Studies will be
performed to examine the roles of unique ULK1 phosphorylation sites in the activation of downstream
effectors, including RUNX1, CBFβ and the Core Binding Factor (CBF) complex. The requirement of ULK1 in
the regulation of CHAF1b and CHAF1a in leukemogenesis will be assessed, and the functional role of the
ULK1-S6K complex in mRNA translation and ribosome function in AML cells will be defined. Specific Aim 2 will
determine the role of ULK1 and effector pathways in antileukemic responses in AML models in vivo. AML
models will be established using ULK1 conditional knockout mice and AML patient-derived xenografts. The
impact of ULK1, as well as ULK1 effector pathways in leukemogenesis and generation of antileukemic
responses by hypomethylating agents and chemotherapeutic agents will be examined. Specific aim 3 will
examine the antileukemic properties of novel ULK1 inhibitors on primary leukemic progenitors from AML
patients. It will systematically study the effects of ULK1 inhibitors on primary cells from A...

## Key facts

- **NIH application ID:** 10801240
- **Project number:** 2I01CX000916-09A2
- **Recipient organization:** JESSE BROWN VA MEDICAL CENTER
- **Principal Investigator:** LEONIDAS C. PLATANIAS
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 2
- **Project period:** 2013-07-01 → 2027-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10801240

## Citation

> US National Institutes of Health, RePORTER application 10801240, Signaling Pathways and Therapeutic Targeting of Leukemic Cells (2I01CX000916-09A2). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10801240. Licensed CC0.

---

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