Elucidating metabolic alterations in myeloproliferative neoplasms: implications for treatment

Yan, Fei (2025) Elucidating metabolic alterations in myeloproliferative neoplasms: implications for treatment. PhD thesis, University of Glasgow.

Abstract

Myeloproliferative neoplasms (MPN) are haematopoietic disorders leading to aberrant expansion of myeloid, erythroid and megakaryocytic lineages, which are classified into three phenotypes namely Polycythaemia Vera (PV), Essential Thrombocythemia (ET) and Primary Myelofibrosis (PMF). The three main somatic mutations leading to MPN are Janus Kinase 2 V617F (JAK2V617F), Janus Kinase 2 exon 12 and Calreticulin (CALR). JAK2V617F was the first driver mutation found in MPNs, with a mutation rate of 95%/60%/55% in PV, ET and PMF respectively. Janus Kinase 2 is one of the four Janus proteins that are constructed to transmit signals from cytokines to downstream pathways. Inside normal cells, Janus Kinase 2 has a dual kinase structure with two domains: an active tyrosine kinase domain JH1 and a catalytically inactive pseudokinase domain JH2. Both domains interact with each other, depending on cellular context with JH2 inhibiting JH1 in the absence of cytokines. In MPN, these mutations lead to the inhibition of JH1 and constitutive activation of downstream signalling pathways including STAT5, RAS/MAPK and PI3K/Akt/mTOR pathways in the absence of growth factors. The discovery of JAK2 inhibitors is beneficial for improving the disease phenotype, but do not eliminate the persistent blood cancer stem cells, which are the cause of the disease. It is therefore important, to find novel therapeutic ways to target blood cancer stem cells. To sustain accelerated growth rate, cancer cells need abnormally high amounts of energy, taken up as nutrients (e.g. glucose), and to increase the breakdown of such nutrients through metabolic pathways. In addition, cancer cells often alter the amount of oxygen they require for the purpose of growing rapidly. Cancer cells therefore alter normal cellular metabolic pathways. Importantly, relying on these alterations makes them vulnerable and targeting altered metabolism and oxygen consumption is an attractive approach to eliminate cancer therapeutically.

My data indicate that metabolic processes are deregulated in MPN. In this thesis, experiments have been performed using advanced assays including Seahorse Metabolic Flux Assay, Liquid Chromatography-Mass Spectrometry, and Flow-cytometry. C57BI/6 background JAK2V617F mice bone marrow cells were used. We have found the increased oxidative phosphorylation and glycolysis rates in MPN Homozygous and heterozygous mice c-kit+ cells. Furthermore, three solute carriers—SLC25A37, SLC2A4, and SLC43A1—were highly expressed in HSCs from homozygous mice, suggesting that targeting glutamine as an anaplerotic pathway could be a potential therapeutic approach.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Additional Information: Supported by funding from an NHS endowment grant.
• Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Funder's Name: NHS
• Supervisor's Name: Kirschner, Dr. Kristina and Helgason, Professor Vignir
• Date of Award: 2025
• Depositing User: Theses Team
• Unique ID: glathesis:2025-84903
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 17 Feb 2025 13:23
• Last Modified: 17 Feb 2025 13:23
• Thesis DOI: 10.5525/gla.thesis.84903
• URI: https://theses.gla.ac.uk/id/eprint/84903