investigation of cyclopentenone prostaglandins and associated receptor GPR44 in acute myeloid leukemia

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- Author:
- Qian, Fenghua
- Graduate Program:
- Pathobiology
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- August 30, 2022
- Committee Members:
- Robert Paulson, Major Field Member
Kumble Prabhu, Chair & Dissertation Advisor
John Vanden Heuvel, Major Field Member
Anthony Paul Schmitt, Professor in Charge/Director of Graduate Studies
Vishal Singh, Outside Unit & Field Member - Keywords:
- leukemia
selenium
cyclopentenone prostaglandin
crth2
DP2
PPARγ
interleukin-4
androgen receptor
EPHA7
RTK
tumor microenvironment
leukemic stem cell - Abstract:
- The relapse of acute myeloid leukemia (AML) remains a significant concern due to the persistent leukemia-initiating cells (LICs) that are not targeted by existing therapies. It is imperative for researchers to find novel treatments that can target LICs to cure AML through complete remission. In this dissertation, a murine model of mixed lineage leukemia (MLL)-AF9 oncogene-induced AML, patient AML cells, and an AML cell line MOLM13 were utilized to study mechanisms of targeting LICs. First, the anti-leukemic effect of cyclopentenone prostaglandins (CyPGs) exogenously administered, endogenously induced by interleukein-4 (IL-4), or dietary selenium (Se) supplementation was demonstrated to effectively bring about a significant decrease in AML through selective targeting of LICs. Furthermore, mechanistic investigation led us to implicate that activation of an intracellular receptor, peroxisome proliferator-activated receptor gamma (PPARγ), and a cell membrane-bound G-protein coupled receptor GPR44 led to apoptosis of AML-LICs. Guided by next generation sequencing methods followed by other functional assays, the ability of GPR44 to negatively regulate receptor tyrosine kinase (RTK) activity as well as KRAS-dependent mechanisms in LICs was confirmed. Second, a compensatory pathway of generation of endogenous CyPGs induced upon deletion of GPR44 in tumor microenvironment (TME) to target AML-LICs was shown to delay the engraftment of leukemia cells in the bone marrow. Finally, sex disparity in our studies with AML cells and TME indicated that interaction of androgen and androgen receptor (AR) also contributed to the increased aggressiveness of AML of female origin. In addition, our studies for the first time, demonstrated that the expression of GPR44 was negatively correlated with AR expression. Taken together, these studies highlight the novel role of GPR44, as a key sensor of CyPGs, to activate pathways of apoptosis in LICs. These preclinical studies are poised to further our mechanistic understanding of the anti-leukemic role of CyPGs and their use in the treatment of leukemia.
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