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Characterization of granulocyte-macrophage colony-stimulating factor signaling in RUNX1-ETO leukemogenesis

By Stephanie Weng

Abstract

The t(8;21)(q22;q22) generates the oncofusion protein RUNX1-ETO (AML1-ETO, RUNX1-RUNX1T1, AML1-MTG8) and is one of the most common chromosomal abnormalities associated with acute myeloid leukemia (AML). Loss of a sex chromosome (LOS) is detected in 32-59% of t(8;21) AML patients, which suggests haploinsufficiency of key tumor suppressors on the sex chromosomes may be involved in t(8;21) leukemogenesis. Though LOS is frequently observed in t(8;21) patients, there have been no mechanistic studies examining its role in the pathogenesis of t(8;21) AML. The gene encoding the granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor, CSF2RA, is located on the sex chromosomes. With LOS, t(8;21) cells suffer haploinsufficiency of CSF2RA, resulting in reduced GM-CSF signaling. It was recently discovered that GM-CSF signaling, which is compromised upon LOS, inhibits t(8;21) leukemogenesis. Therefore, this dissertation explores the mechanisms by which GM-CSF signaling prevents t(8;21) leukemogenesis and aims to identify mediating mechanisms that are therapeutically targetable. Gene expression profiling of GM-CSF-treated RUNX1-ETO cells revealed that GM-CSF signaling elicits a unique gene expression profile in RUNX1-ETO cells. This gene expression profile correlates with attenuated MYC-associated gene signatures and human myelopoiesis, which together reduce the self-renewal potential of RUNX1-ETO cells and inhibit leukemogenesis. To identify GM-CSF-induced genes mediating the inhibition of RUNX1-ETO leukemogenesis, a functional screen was conducted to identify several genes, including Mxi1, which reduce the self-renewal potential of RUNX1-ETO cells. MXI1 is a well-established inhibitor of MYC; therefore, the effects of MXI1 and MYC inhibition were examined in t(8;21) cells. It was found that MYC inhibition promotes apoptosis and reduces the proliferation and self-renewal potential of t(8;21) cells, demonstrating that MYC is critical for maintaining leukemic potential and may serve as an effective target in t(8;21) AML treatment. Furthermore, it was discovered that in addition to being downregulated upon LOS-driven haploinsufficiency, CSF2RA is also downregulated in t(8;21) cell lines through its 3’ UTR. This reveals an additional mechanism present in t(8;21) cells to reduce GM-CSF signaling and promote leukemogenesis. Together, these studies highlight the importance of GM-CSF signaling in attenuating MYC in t(8;21) cells and elucidate the mechanisms by which t(8;21) cells downregulate CSF2RA to reduce GM-CSF signaling

Topics: Cellular biology, GM-CSF, Leukemia, RUNX1-ETO, t(8, 21)
Publisher: eScholarship, University of California
Year: 2016
OAI identifier: oai:escholarship.org/ark:/13030/qt7ng0j12n
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