# Crosstalk between leukemic blasts and the BM microenvironment contribute to leukemic transformation

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2022 · $368,485

## Abstract

PROJECT SUMMARY
Acute myeloid leukemia (AML) is a clonal, highly heterogeneous malignancy of the blood and bone marrow with
poor prognosis. Along with genetic mutations within the leukemic cells themselves, alterations in the BM
microenvironment (BMM) also play an important role in leukemia transformation, therapy resistance, and
relapse. Thus, to develop effective AML therapies, it is critical to understand how intrinsic genetic alterations in
the leukemic blasts cooperate with the BMM to facilitate leukemogenesis. We identified that the secreted protein
Epithelial Growth Factor Like 7 (EGFL7) is highly expressed in a large cohort of AML patients and is associated
with poor prognosis. We further demonstrate that: 1) EGFL7 protein increases blast cell growth and impacts on
leukemic stem cell (LSC) function; 2) leukemic bone marrow mesenchymal stromal cells (MSCs) express and
secrete EGFL7 at increased levels compared to normal MSCs ; 3) normal MSCs exhibit increased growth and
survival in response to a recombinant EGFL7 protein and 4) Egfl7 is increased in AML blasts, but not in pre-
leukemic hematopoietic stem and progenitor cells (HSPCs) from a primary Mll PTD; Flt3 ITD murine AML model.
Based on our work, we hypothesize that aberrant EGFL7 expression by leukemic cells and BM niche cells
contribute to leukemogenesis and is a relevant target for treatment for AML patients. The goal of our proposal is
to fully characterize the phenotypic contributions of EGFL7 to myeloid leukemogenesis, dissect its molecular
mechanism(s), and determine the therapeutic benefit of targeting EGFL7 in AML. We are planning to achieve
these goals through the following specific aims (SA): SA#1: To demonstrate the importance of EGFL7 in
leukemic cells to alter the BM microenvironment to promote leukemogenesis. Here, we hypothesize that EGFL7
promotes a positive feedback loop between leukemic cells and the BM microenvironment contributing to disease
initiation and progression. We will test this hypothesis with a series of in vitro and in vivo experiments organized
in three tasks. In Task 1 we will examine the contribution of EGFL7 in the BMM towards the initiation of AML
using our Mll PTD; Flt3 ITD and Egfl7fl/fl conditional knock-out mouse models. For Task 2 we will determine how
alterations in the expression of EGFL7 effects MSCs in leukemogenesis. Task 3 we will characterize the
molecular mechanisms of Egfl7-dependent signaling pathways in MSCs; SA#2: To investigate anti-leukemic
activity of a monoclonal EGFL7 blocking antibody (Parsatuzumab) in combination with a FLT3 inhibitor
(Gilteritinib), using patient derived xenograft (PDX) murine models and primary genetic murine models of AML.
Here, we propose to conduct in vitro and in vivo preclinical studies using AML cell lines, primary AML samples
and two murine models of FLT3 mutated AML to evaluate the efficacy of targeting the autocrine and paracrine
action of EGFL7 in AML. Overall, this proposal seeks to define the r...

## Key facts

- **NIH application ID:** 10446917
- **Project number:** 1R01CA259182-01A1
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Adrienne M. Dorrance
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $368,485
- **Award type:** 1
- **Project period:** 2022-03-04 → 2027-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10446917

## Citation

> US National Institutes of Health, RePORTER application 10446917, Crosstalk between leukemic blasts and the BM microenvironment contribute to leukemic transformation (1R01CA259182-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10446917. Licensed CC0.

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