# Project 3: Modeling Malignant Myelopoiesis to Increase Efficacy of Targeted Leukemia Therapy

> **NIH NIH U54** · UNIVERSITY OF CALIFORNIA-IRVINE · 2021 · $395,609

## Abstract

Project 3 Summary
Chronic myeloid leukemia (CML), one of the most prevalent of human leukemias, is a natural model of
dysregulated granulopoiesis driven by the BCR-ABL1 tyrosine kinase. Whereas tyrosine kinase inhibitors
(TKIs) such as imatinib have dramatically improved the prognosis in CML, lifelong treatment is needed, with a
corresponding large economic impact on the health care system. The two biggest unaddressed questions in
the field of CML therapeutics are to understand the mechanism of primary resistance to TKI therapy, and to
identify strategies to increase the rate that patients remain in molecular remission after discontinuation of TKI
therapy, possibly representing permanent cure of the disease. The Scientific Premise of this Project is that new
and clinically relevant insights into the biology of CML and its response to therapy can be gained by a more
physiologically accurate mathematical model of the disease. The first Aim of this Project will leverage UCI's
extensive expertise in mathematical modeling of complex biological phenomena to develop more sophisticated
models of CML that incorporate physiologically relevant homeostatic feedback and feedforward regulatory
interactions between normal and leukemic cells, and between stem cells and more differentiated cells. Optimal
model structures will be vetted by a machine-based automated model selection process to arrive at a model
that maintains appropriate stability and homeostasis, responds physiologically to stress and depletion of
different cell compartments, and conforms to the limited existing qualitative data on CML hematopoiesis
derived from mouse models and patient studies. In the second Aim, an innovative binary BCR-ABL1 transgenic
mouse model will be used to determine for the first time the relevant parameters governing the production of
the malignant blood cells in CML. Single-cell transcriptome analysis of normal and malignant hematopoietic
stem/progenitor populations, including the heterogeneous multi-potential progenitor compartment, will generate
important new knowledge about the heterogeneity of CML myelopoiesis and provide insight into the molecular
mechanisms of feedback/feedforward regulation. Based on these preclinical studies, a novel clinical trial to
gain insight into similar cell kinetic parameters in CML patients will be initiated. In the final Aim, certain
predictions from the validated mathematical model will be tested in the transgenic mouse model. Among the
hypotheses that can be tested straightaway are that the original burden of leukemic stem cells governs the
initial response to TKI therapy and represents and important prognostic factor, and that treatments that
stimulate leukemic stem cell cycle entry are optimally delivered intermittently rather than continuously.
Additional hypotheses emerging from the modeling effort will be tested in years 3-5 of the grant. Together, the
studies proposed in this Project will provide critical new knowledge about the...

## Key facts

- **NIH application ID:** 10136548
- **Project number:** 5U54CA217378-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** RICHARD A. VAN ETTEN
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $395,609
- **Award type:** 5
- **Project period:** 2018-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10136548

## Citation

> US National Institutes of Health, RePORTER application 10136548, Project 3: Modeling Malignant Myelopoiesis to Increase Efficacy of Targeted Leukemia Therapy (5U54CA217378-04). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10136548. Licensed CC0.

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