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Characterization of the role of TKTL1 in Acute Monocytic Leukaemia

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Universitat de Barcelona. Departament de Bioquímica i Biomedicina Molecular

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[eng] Leukaemia is one of the types of cancer where treatment resistance is prevalent. Better understanding of leukemic cells metabolism opens possibilities for new therapeutic strategies and better prognosis stratification. Leukaemia arises from many different genetic alterations, that affect distinct cellular processes, all driving leukemogenesis. Many of these result in a phenotype that grants metabolic advantages amidst the hypoxic conditions of the haematopoietic niche of the bone marrow, the point of origin of all types of this cancer. In order to understand the metabolic reprogramming that grants these advantages, we performed metabolic characterization in vitro of cell lines of acute monocytic leukaemia (THP1) and chronic myeloid leukaemia (HAP1), with focus on the role of Transketolase-like 1 (TKTL1) and ten-to-eleven Methylcytosine dioxygenase 2 (TET2), respectively, on both normoxic and hypoxic experimental settings.
We revealed that TKTL1 is a key enzyme in the metabolic reprogramming of the hypoxia adaptation, driving proliferation, higher glycolytic rates, higher glutamine consumption and subsequent glutamate production. Our results also showed the altered metabolism of many amino acids and biogenic amines, that grant more substrates for nucleotides synthesis, higher stress tolerance and manipulation of the immune response of the microenvironment. It also highlighted the vulnerabilities that arise from focusing on targeting TKTL1 for therapy and possible secondary targetable metabolic pathways for future therapies.
Additionally, we demonstrated the effects of the loss of TET2 in the leukemic cells through a tracer-based metabolomics approach, showing how its mutation primes the cells to shift their metabolism at a higher cost for their ROS homeostasis, a known hallmark of cancer which increases the risk of more mutations occurring due to genomic instability. This allowed us to create a metabolic map of the changes induced by the loss of TET2,
 
as a blueprint for new therapeutic venues in leukaemias that have this mutational hit.
Together, the thesis presented here contributes to the knowledge of the mechanisms underlying metabolic reprogramming of leukaemia according to specific mutational genotypes and how they open new possible therapies for patients that develop resistance.

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(c) Baptista, Inês do Carmo Viegas, 2022

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Tesis Doctorals - Departament - Bioquímica i Biomedicina Molecular

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Characterization of the role of TKTL1 in Acute Monocytic Leukaemia