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PhD Dissertation Defense - Nour Madhoun

Start Date: April 13, 2017
End Date: April 13, 2017

​​ADVISOR: Professor Jasmeen Merzaban
Effects of CD44 Ligation on Signaling and Metabolic Pathways in Acute Myeloid Leukemia
DATE: Thursday, April 13, 2017
TIME: 6:00 - 7:00 p.m.
LOCATION: Building 2 · Level 5 · Room 5209

Acute myeloid leukemia (AML) is characterized by the accumulation of immature hematopoietic cells blocked at various stages of differentiation. CD44-ligation using anti-CD44 monoclonal antibodies (mAbs) has been shown to reverse the blockage of differentiation and to inhibit the proliferation of blasts in most AML-subtypes. However, the molecular mechanisms underlying this property have not been fully elucidated. In the dissertation, we sought to I) analyze the effects of anti-CD44 mAbs on downstream signaling pathways, including the ERK1/2 (extracellular signal-regulated kinase 1 and 2) and mTOR (mammalian target of rapamycin) pathways during AML differentiation and II) use state-of-the-art Nuclear Magnetic Resonance (NMR) technology to determine the global metabolic changes that take place upon induction of differentiation of AML cells using anti-CD44 mAbs and two previously reported differentiation agents, retinoic acid (RA) and granulocyte-colony stimulating factor (G-CSF). Our studies provide evidence that CD44-ligation with specific mAbs in AML cells induced an increase in ERK1/2 phosphorylation. The use of the MEK inhibitor (U0126) significantly inhibited the CD44-induced differentiation of HL60 cells, suggesting that ERK1/2 is critical for the CD44-triggered differentiation in AML. In addition, this was accompanied by a marked decrease in the phosphorylation of the mTORC1 and mTORC2 complexes, which are strongly correlated with the inhibition of the PI3K/Akt pathway. NMR experiments demonstrated that considerable changes in the metabolic profiles of HL60 cells were induced in response to each differentiation agent. These most notable metabolites that significantly changed upon CD44 ligation were involved in the tricarboxylic acid (TCA) cycle and glycolysis such as, succinate, fumarate and lactate. Therefore, we sought to analyze the mechanisms underlying their alterations. Our results revealed that anti-CD44 mAbs treatment induced upregulation in fumarate hydratase (FH) expression and its activity which was accompanied by a decrease in succinate dehydrogenase (SDH) activity. Interestingly, our results indicated that FH induced by anti-CD44 mAb is regulated through the activation of the ERK1/2 pathway.  Therefore, our findings highlight new elements in support for the use of anti-CD44 mAbs in AML therapies and open new perspectives to use metabolic profiling as a tool to support the potential possibilities for the development of CD44-targeted therapy of AML.

 Nour graduated with honors in Biotechnology and Genetics Engineering from Jordan University of Science and Technology (JUST), Irbid, Jordan in 2008. She joined the Bioscience MSc program as part of KAUST founding class. On 2011, she started her Ph.D. in the same program. During the Ph.D., she worked on studying the signaling and metabolic pathways in Acute Myeloid Leukemia. Nour is a recipient of the Academic Excellence Award (AEA) during her PhD program at KAUST.