Epidermal Growth Factor-Like 7 Modulation of Mesenchymal Stromal Cells in Acute Myeloid Leukemia
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Publisher:The Ohio State University
Series/Report no.:The Ohio State University. Department of Molecular Genetics Undergraduate Research Theses
Acute myeloid leukemia (AML) is a malignant hematological disease of the bone marrow (BM) characterized by clonal expansion of immature stem and progenitor cells. AML has a poor prognosis, highlighting the need for efficient therapeutic strategies to completely eradicate the disease. Recently, the BM microenvironment (BMM), and specifically mesenchymal stromal cells (MSCs) within the BMM, have been shown to contribute to myeloid malignancies. Our lab has shown that expression of Epidermal Growth Factor-Like 7 (Egfl7), an angiogenic protein secreted in the BMM, leads to poor prognosis in AML. However, the role of Egfl7 in leukemic MSCs has yet to be investigated. To mimic the phenotype of human AML, we used a murine double knock-in model targeting two commonly rearranged genes found in AML: Kmt2a and Flt3. This model (PTD/ITD) harbors a Kmt2a-partial tandem duplication (Kmt2a-PTD) and an Flt3-internal tandem duplication (Flt3-ITD), which together develop acute leukemia with 100% penetrance. Our data demonstrate that EGFL7 is expressed in the healthy human Bone marrow stromal cells (BMSCs), specifically in one of six subpopulations of the leptin receptor positive (LepR+) MSC populations. In human AML BMSCs, we show that EGFL7 expression is increased compared to healthy BM. Using our murine AML model, we found PTD/ITD MSCs also had increases in Egfl7 mRNA and EGFL7 protein levels compared to wild type (WT) MSCs. Additionally, rEGFL7 treatment increased the proliferation of MSCs, while absence of Egfl7 caused decreased MSC proliferation potential. Finally, we demonstrate that deletion of Egfl7 promoted MSC adipogenic differentiation over chondrocyte differentiation. Thus, we hypothesize that increased Egfl7 expression acquired in AML blasts results in increased MSC proliferation and survival, leading to a positive feedback loop between AML blasts and MSCs and resulting in poor prognosis to standard therapies. Therefore, we believe future therapies targeting EGFL7 in both AML blasts and the BMM will more efficiently eliminate disease persistence and relapse in patients with AML.
Academic Major: Molecular Genetics
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