# Mechanisms and targeting of inflammatory cytokine-driven expansion and progression in AML

> **NIH NIH U01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2024 · $277,069

## Abstract

PROJECT SUMMARY/ABSTRACT
Acute myeloid leukemia (AML) continues to have a dismal 5-years survival rate of <25% with chemotherapy.
Those who survive suffer lifelong consequences, largely due to complications from chemotherapy, and disease
relapse is inevitable. Thus, there is an urgent need for new, improved treatments to eliminate AML cells rapidly
and completely. Since AML is a highly heterogeneous disease caused by multiple mutations, we propose that
a common, targetable feature among AML cases is that they are directly and indirectly influenced by cytokines
secreted in the bone marrow microenvironment. Our long-term goal is to identify novel drug targets to
selectively eradicate malignant clones that may impact the response to AML therapies. Our immediate goals
are to comprehensively determine the molecular mechanisms by which inflammatory pathways promote clonal
evolution in AML. We found that the inflammatory cytokine interleukin-1β (IL-1β), which is elevated in a diverse
set of AML patients, both encourages AML cells to multiply and simultaneously impedes normal cell growth.
Blocking communication between AML cells and IL-1 inhibits these effects and reduces survival of AML cells
while sparing healthy progenitors. Because cells from a majority of AML patients with different genetic
subtypes are dependent on IL-1 signaling for their survival, we predict that a large percentage of AML patients
might benefit from drugs targeting this pathway. However, direct targeting of IL-1 signaling may impact cellular
functions in healthy cells. We therefore focused our study on defining the IL-1-mediated molecular differences
between AML and healthy progenitors. Gene expression analysis identified that IL-1 upregulates ASF1B and
MARCKS in AML compared to healthy progenitors. ASF1B and MARCKS regulate cell proliferation, DNA
damage response, and inflammation in AML. Our data shows that genetic and pharmacological targeting of
ASF1B and MARCKS pathways suppresses AML growth. These findings suggest a number of important new
research directions. In the proposed project, we will test the hypothesis that differential activation of ASF1B
and MARCKS by IL-1β in AML versus healthy progenitors provides a competitive advantage to leukemic cells,
which ultimately leads to AML progression. Specifically, we will determine: (1) the in vitro mechanisms by
which IL-1 activation of ASF1B and MARCKS promotes the growth of AML cells; (2) the roles of ASF1B and
MARCKS in conferring IL-1-mediated growth advantage and driving AML progression in vivo; and (3) the
validity of ASF1B and MARCKS as therapeutic targets in AML using available small-molecule inhibitors. To
achieve our goals we established a variety of tools including 4 new transgenic mouse models and access to
TLK and MARCKS inhibitor through collaborations with world-renowned leaders. Determining the underlying
molecular mechanisms by which IL-1 supports AML development will pave the way to designing new treatment
st...

## Key facts

- **NIH application ID:** 10796870
- **Project number:** 5U01CA229875-06
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Anupriya Agarwal
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $277,069
- **Award type:** 5
- **Project period:** 2019-03-01 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10796870

## Citation

> US National Institutes of Health, RePORTER application 10796870, Mechanisms and targeting of inflammatory cytokine-driven expansion and progression in AML (5U01CA229875-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10796870. Licensed CC0.

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