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Insights into Acute Myeloid Leukaemia metabolism using NMR Spectroscopy
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A Leucemia Mielóide Aguda (LMA) é o segundo tipo de leucemia mais
diagnosticado e o mais comum entre adultos. É uma condição hematológica caracterizada pela infiltração da medula óssea e do sangue por populações clonais de células mielóides imaturas, anormalmente diferenciadas e altamente proliferativas. É uma doença muito
heterogénea, originando-se a partir de uma grande variedade de linhagens hematopoiéticas, com perfis genéticos distintos.(2,3)
Uma das apresentações menos comuns desta doença é a acidose láctica
(acumulação de lactato no sangue), relacionada com um mau prognóstico de sobrevivência.(4) Esta condição está relacionada com elevadas taxas de glicólise aeróbica, o “efeito de Warburg”, resultando na produção de lactato que é excretado para o microambiente. Vários estudos demonstram que alguns tipos de células tumorais incorporam lactato e utilizam-no como base para o metabolismo oxidativo. (5,6)
Estudou-se o metabolismo de lactato e glucose de três linhagens de LMA (HL60, THP1 e HEL) através de RMN. Investigou-se também a influência do VEGF (importante no microambiente tumoral, estando envolvido no processo de angiogénese em LMA) nestas linhas celulares.(7)
Os resultados demonstraram que as linhas promielocítica e monocítica conseguem utilizar o lactato como base para a manutenção das suas necessidades energéticas e de biomassa, utilizando-o como substrato para o ciclo de Krebs e para a fosforilação oxidativa. Observámos que a linha monocítica metaboliza a glucose através da glicólise e da via das pentoses fosfato. A linha eritroleucémica depende da presença de glucose, sendo incapaz de suster o seu metabolismo usando o lactato como substrato. O VEGF parece ter um efeito positivo nas linhas HL60 e THP1, potenciando as taxas de glicólise e promovendo a produção de nucleótidos, o que sugere que o VEGF pode ter influência neste padrão metabólico alterado. Assim, as três linhagens de LMA apresentam diferentes graus de plasticidade metabólicas, tendo algumas se adaptado para tirar partido do microambiente, enquanto que outras parecem incapazes de se ajustar.
Também investigámos como a exposição a diferentes microambientes influencia o metabolismo da LMA. O microambiente natural dos blastos de LMA encontra-se na medula óssea mas as células podem espalhar-se e acumular-se noutras zonas do corpo onde, para sobreviver, têm de se adaptar a um microambiente diferente. Em alguns casos, a LMA resulta na infiltração do Sistema Nervoso Central, normalmente afectando as
meninges. (1)
Células HEL foram inoculados na medula e cérebro de ratinhos e, através de análise multivariada de espectros de RMN, foi possível fazer a distinção entre os perfis metabólicos das células expostas a cada um dos microambientes. Os resultados mostraram que esta linhagem está melhor adaptada para sobreviver no microambiente da medula do que no microambiente cerebral. Em ambos os microambientes observaram-se
alterações graduais no metabolismo resultantes de mais tempo de exposição, demonstrando que o metabolismo celular não é estático, sendo influenciado pelas características do meio envolvente.
Em conclusão, foi demonstrado que a elucidação do metabolismo de leucemia e da sua interacção com o microambiente é indispensável à caracterização desta doença e pode contribuir para esclarecer os mecanismos biológicos responsáveis pelo seu desenvolvimento e progressão.
Acute Myeloid Leukemia (AML) is the second most diagnosed type of leukemia and the most common in adults. It is a haematological disorder characterized by the bone marrow and peripheral blood infiltration of clonal populations of abnormally differentiated and highly proliferative blasts. It is a very heterogenous disease, originating from a wide variety of haematopoietic lineages with a diverse genetic landscape.(2,3) One of the less typical presentations of AML involves lactic acidosis (the accumulation of lactate in the blood) which has been correlated with poor survival prognosis. (4) This condition is correlated with high rates of aerobic glycolysis, the “Warburg effect”, resulting in the production of lactate that is excreted to the microenvironment. Several studies have found that some cancer cells have can take up lactate and utilize it as a source for oxidative metabolism.(5,6) We studied the glucose and lactate metabolism of three different AML lineages (HL60, THP1 and HEL) through NMR spectroscopy. We also investigated the influence of VEGF (another key player in tumour microenvironment, known to be involved in tumour-related angiogenesis in AML) in these cell lines.(7) Our results showed that the promyelocytic and monocytic lines can rely on lactate to sustain their energy and biomass demands, utilizing it as substrate for the TCA cycle and oxidative phosphorylation. On the monocytic line we confirmed that glucose is mainly metabolized through glycolysis and pentose phosphate pathway. The erythroleukemic line was unable to sustain its metabolism on lactate consumption, being dependent on glucose to sustain the cells’ metabolism. VEGF seem to have a positive effect on the HL60 and THP1 lines, increasing glycolytic rates and promoting nucleotide production, which suggest that it may have a role in supporting the alternative metabolism exhibited by these cells. So, the three lineages of AML display very different metabolic plasticity, with some having adapted to take advantage of their environment, while others seeming unable to adjust. We also investigated how exposure to different microenvironments influences AML cell metabolism. The normal environment of AML is the bone marrow (BM), but the cells can spread and accumulate in other organs of the body, where they are required to adapt to a completely different environment. In some cases, AML can involve infiltration of the Central Nervous System, usually in the form of leptomeningeal disease.(1) We inoculated HEL cells into the brain and BM of mice and, through multivariate analysis of NMR data, were able to distinguish between the metabolic profiles of the cells exposed to the two environments. Our results showed that the HEL cell line is much better suited to survive in the BM microenvironment than in the brain microenvironment. In both microenvironments, there were gradual metabolic modifications as the result of increased exposure, indicating that cell metabolism is not static and is influenced by the characteristics of the surrounding microenvironment. In conclusion, we showed that understanding leukaemia metabolism and its interaction with the microenvironment is indispensable for disease characterization and can provide valuable insights into the biologic mechanisms that govern AML progression and survival.
Acute Myeloid Leukemia (AML) is the second most diagnosed type of leukemia and the most common in adults. It is a haematological disorder characterized by the bone marrow and peripheral blood infiltration of clonal populations of abnormally differentiated and highly proliferative blasts. It is a very heterogenous disease, originating from a wide variety of haematopoietic lineages with a diverse genetic landscape.(2,3) One of the less typical presentations of AML involves lactic acidosis (the accumulation of lactate in the blood) which has been correlated with poor survival prognosis. (4) This condition is correlated with high rates of aerobic glycolysis, the “Warburg effect”, resulting in the production of lactate that is excreted to the microenvironment. Several studies have found that some cancer cells have can take up lactate and utilize it as a source for oxidative metabolism.(5,6) We studied the glucose and lactate metabolism of three different AML lineages (HL60, THP1 and HEL) through NMR spectroscopy. We also investigated the influence of VEGF (another key player in tumour microenvironment, known to be involved in tumour-related angiogenesis in AML) in these cell lines.(7) Our results showed that the promyelocytic and monocytic lines can rely on lactate to sustain their energy and biomass demands, utilizing it as substrate for the TCA cycle and oxidative phosphorylation. On the monocytic line we confirmed that glucose is mainly metabolized through glycolysis and pentose phosphate pathway. The erythroleukemic line was unable to sustain its metabolism on lactate consumption, being dependent on glucose to sustain the cells’ metabolism. VEGF seem to have a positive effect on the HL60 and THP1 lines, increasing glycolytic rates and promoting nucleotide production, which suggest that it may have a role in supporting the alternative metabolism exhibited by these cells. So, the three lineages of AML display very different metabolic plasticity, with some having adapted to take advantage of their environment, while others seeming unable to adjust. We also investigated how exposure to different microenvironments influences AML cell metabolism. The normal environment of AML is the bone marrow (BM), but the cells can spread and accumulate in other organs of the body, where they are required to adapt to a completely different environment. In some cases, AML can involve infiltration of the Central Nervous System, usually in the form of leptomeningeal disease.(1) We inoculated HEL cells into the brain and BM of mice and, through multivariate analysis of NMR data, were able to distinguish between the metabolic profiles of the cells exposed to the two environments. Our results showed that the HEL cell line is much better suited to survive in the BM microenvironment than in the brain microenvironment. In both microenvironments, there were gradual metabolic modifications as the result of increased exposure, indicating that cell metabolism is not static and is influenced by the characteristics of the surrounding microenvironment. In conclusion, we showed that understanding leukaemia metabolism and its interaction with the microenvironment is indispensable for disease characterization and can provide valuable insights into the biologic mechanisms that govern AML progression and survival.
Descrição
Palavras-chave
LMA Metabolismo do cancro Microambiente tumoral Ciências biomédicas Biologia molecular
Contexto Educativo
Citação
Editora
Instituto de Higiene e Medicina Tropical