Project title: Targeting autophagy and aberrant mitochondrial folate metabolism in leukemic stem cells

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Chronic myeloid leukemia (CML) is a myeloproliferative disease consisting of a small number of cancer-causing leukemic stem cells (LSCs) and a variety of mature progenitors. LSCs represent the top of the differentiation hierarchy, responsible for the accumulation of blast cells and driving hematologic relapse. CML development begins with the acquisition of the Philadelphia chromosome (Ph) in a singular pluripotent hematopoietic stem cell (HSC). The Ph is a fusion of chromosomes 9 and 22, causing the formation of BCR-ABL, the chimeric proto-oncogene responsible for HSC transformation. BCR-ABL is a constituently active tyrosine kinase (TK), whose activity perturbs and enhances pathways well established to be involved in the cancer signalling, such as JAK/STAT, PI3K/AKT and RAS/MEK. The CML therapeutic landscape is dominated by tyrosine kinase inhibitors (TKIs), blocking the interactions between BCR-ABL and ATP thus abolishing downstream signalling pathways. The first TKI developed to treat CML in such a way was imatinib, developed and trialled in the late 1990s, to this day it still remains a standard treatment. The majority of patients treated with imatinib in the chronic phase respond strongly to treatment, with BCR-ABL transcripts drastically lowering in abundance with the potential to reach undetectable levels. A study by O'Brien et al., 2003 showed that after 18 months of treatment with imatinib, 87.1% of patients showed a major cytogenic response, while 76.2% of patients showed a complete cytogenic response. Despite patients showing excellent responses to TKI treatment, discontinuation of imatinib treatment is frequently followed by cytogenic and hematologic relapse, suggesting that BCR-ABL inhibition on its own is not a curative approach. Most CML patients require lifelong TKI treatment to prevent relapse, this is far from ideal given the vascular complications caused by second generation TKIs and the potential for the development of secondary resistance. It is hypothesised that relapse occurs upon cessation of TKI treatment due to the survival of a population of quiescent LSCs which possess BCR-ABL independent survival pathways, rendering this subset of LSCs immune to TKI-induced apoptosis. Even though the initial oncogenic impetus for the development of CML is the acquisition of the Ph, BCR-ABL signalling is not the sole pathway responsible for the persistence of LSCs post-transformation. BCR-ABL independent survival of LSCs is associated with a number of cellular changes, such as aberrant signalling though NF-kB and Beta-catenin, and deregulation of mitochondrial function relating to central carbon metabolism, oxidative phosphorylation and autophagy. The importance of this mitochondrial dysfunction for the survival of LSCs has been demonstrated by the selective eradication of CML LSCs both in vitro and in a xenotransplantation model of human CML using imatinib and tigecycline, an antibiotic which inhibits mitochondrial protein translation. This project therefore aims to further characterize the aberrant metabolic function exhibited by TKI resistant LSCs, and to use this increased resolution to identify and validate targets which can be used to selectively eliminate LSC populations.