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1.
Blood ; 141(21): 2553-2565, 2023 05 25.
Artículo en Inglés | MEDLINE | ID: mdl-36634302

RESUMEN

Our understanding of cancer metabolism spans from its role in cellular energetics and supplying the building blocks necessary for proliferation, to maintaining cellular redox and regulating the cellular epigenome and transcriptome. Cancer metabolism, once thought to be solely driven by upregulated glycolysis, is now known to comprise multiple pathways with great plasticity in response to extrinsic challenges. Furthermore, cancer cells can modify their surrounding niche during disease initiation, maintenance, and metastasis, thereby contributing to therapy resistance. Leukemia is a paradigm model of stem cell-driven cancer. In this study, we review how leukemia remodels the niche and rewires its metabolism, with particular attention paid to therapy-resistant stem cells. Specifically, we aim to give a global, nonexhaustive overview of key metabolic pathways. By contrasting the metabolic rewiring required by myeloid-leukemic stem cells with that required for hematopoiesis and immune cell function, we highlight the metabolic features they share. This is a critical consideration when contemplating anticancer metabolic inhibitor options, especially in the context of anticancer immune therapies. Finally, we examine pathways that have not been studied in leukemia but are critical in solid cancers in the context of metastasis and interaction with new niches. These studies also offer detailed mechanisms that are yet to be investigated in leukemia. Given that cancer (and normal) cells can meet their energy requirements by not only upregulating metabolic pathways but also utilizing systemically available substrates, we aim to inform how interlinked these metabolic pathways are, both within leukemic cells and between cancer cells and their niche.


Asunto(s)
Hematopoyesis , Leucemia , Humanos , Leucemia/metabolismo , Glucólisis , Oxidación-Reducción , Células Madre Neoplásicas/metabolismo , Nicho de Células Madre
2.
EMBO Rep ; 24(10): e56279, 2023 10 09.
Artículo en Inglés | MEDLINE | ID: mdl-37489735

RESUMEN

To fuel accelerated proliferation, leukaemic cells undergo metabolic deregulation, which can result in specific nutrient dependencies. Here, we perform an amino acid drop-out screen and apply pre-clinical models of chronic phase chronic myeloid leukaemia (CML) to identify arginine as a nutrient essential for primary human CML cells. Analysis of the Microarray Innovations in Leukaemia (MILE) dataset uncovers reduced ASS1 levels in CML compared to most other leukaemia types. Stable isotope tracing reveals repressed activity of all urea cycle enzymes in patient-derived CML CD34+ cells, rendering them arginine auxotrophic. Thus, arginine deprivation completely blocks proliferation of CML CD34+ cells and induces significantly higher levels of apoptosis when compared to arginine-deprived cell lines. Similarly, primary CML cells, but not normal CD34+ samples, are particularly sensitive to treatment with the arginine-depleting enzyme, BCT-100, which induces apoptosis and reduces clonogenicity. Moreover, BCT-100 is highly efficacious in a patient-derived xenograft model, causing > 90% reduction in the number of human leukaemic stem cells (LSCs). These findings indicate arginine depletion to be a promising and novel strategy to eradicate therapy resistant LSCs.


Asunto(s)
Arginina , Leucemia Mielógena Crónica BCR-ABL Positiva , Humanos , Arginina/metabolismo , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Apoptosis , Células Madre/metabolismo , Células Madre Neoplásicas/metabolismo
3.
Nat Commun ; 15(1): 1931, 2024 Mar 02.
Artículo en Inglés | MEDLINE | ID: mdl-38431691

RESUMEN

Supporting cell proliferation through nucleotide biosynthesis is an essential requirement for cancer cells. Hence, inhibition of folate-mediated one carbon (1C) metabolism, which is required for nucleotide synthesis, has been successfully exploited in anti-cancer therapy. Here, we reveal that mitochondrial folate metabolism is upregulated in patient-derived leukaemic stem cells (LSCs). We demonstrate that inhibition of mitochondrial 1C metabolism through impairment of de novo purine synthesis has a cytostatic effect on chronic myeloid leukaemia (CML) cells. Consequently, changes in purine nucleotide levels lead to activation of AMPK signalling and suppression of mTORC1 activity. Notably, suppression of mitochondrial 1C metabolism increases expression of erythroid differentiation markers. Moreover, we find that increased differentiation occurs independently of AMPK signalling and can be reversed through reconstitution of purine levels and reactivation of mTORC1. Of clinical relevance, we identify that combination of 1C metabolism inhibition with imatinib, a frontline treatment for CML patients, decreases the number of therapy-resistant CML LSCs in a patient-derived xenograft model. Our results highlight a role for folate metabolism and purine sensing in stem cell fate decisions and leukaemogenesis.


Asunto(s)
Leucemia Mielógena Crónica BCR-ABL Positiva , Leucemia Mieloide , Humanos , Diana Mecanicista del Complejo 1 de la Rapamicina , Proteínas Quinasas Activadas por AMP , Purinas/uso terapéutico , Nucleótidos de Purina , Ácido Fólico/metabolismo , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico
4.
Nat Commun ; 15(1): 1090, 2024 Feb 05.
Artículo en Inglés | MEDLINE | ID: mdl-38316788

RESUMEN

Macrophages are fundamental cells of the innate immune system that support normal haematopoiesis and play roles in both anti-cancer immunity and tumour progression. Here we use a chimeric mouse model of chronic myeloid leukaemia (CML) and human bone marrow (BM) derived macrophages to study the impact of the dysregulated BM microenvironment on bystander macrophages. Utilising single-cell RNA sequencing (scRNA-seq) of Philadelphia chromosome (Ph) negative macrophages we reveal unique subpopulations of immature macrophages residing in the CML BM microenvironment. CML exposed macrophages separate from their normal counterparts by reduced expression of the surface marker CD36, which significantly reduces clearance of apoptotic cells. We uncover aberrant production of CML-secreted factors, including the immune modulatory protein lactotransferrin (LTF), that suppresses efferocytosis, phagocytosis, and CD36 surface expression in BM macrophages, indicating that the elevated secretion of LTF is, at least partially responsible for the supressed clearance function of Ph- macrophages.


Asunto(s)
Leucemia Mielógena Crónica BCR-ABL Positiva , Leucemia Mieloide , Animales , Ratones , Humanos , Médula Ósea/patología , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Leucemia Mieloide/patología , Cromosoma Filadelfia , Macrófagos/metabolismo , Proteínas de Fusión bcr-abl/genética , Proteínas de Fusión bcr-abl/metabolismo , Microambiente Tumoral/genética
5.
Nat Commun ; 14(1): 4634, 2023 08 17.
Artículo en Inglés | MEDLINE | ID: mdl-37591854

RESUMEN

Deregulated oxidative metabolism is a hallmark of leukaemia. While tyrosine kinase inhibitors (TKIs) such as imatinib have increased survival of chronic myeloid leukaemia (CML) patients, they fail to eradicate disease-initiating leukemic stem cells (LSCs). Whether TKI-treated CML LSCs remain metabolically deregulated is unknown. Using clinically and physiologically relevant assays, we generate multi-omics datasets that offer unique insight into metabolic adaptation and nutrient fate in patient-derived CML LSCs. We demonstrate that LSCs have increased pyruvate anaplerosis, mediated by increased mitochondrial pyruvate carrier 1/2 (MPC1/2) levels and pyruvate carboxylase (PC) activity, in comparison to normal counterparts. While imatinib reverses BCR::ABL1-mediated LSC metabolic reprogramming, stable isotope-assisted metabolomics reveals that deregulated pyruvate anaplerosis is not affected by imatinib. Encouragingly, genetic ablation of pyruvate anaplerosis sensitises CML cells to imatinib. Finally, we demonstrate that MSDC-0160, a clinical orally-available MPC1/2 inhibitor, inhibits pyruvate anaplerosis and targets imatinib-resistant CML LSCs in robust pre-clinical CML models. Collectively these results highlight pyruvate anaplerosis as a persistent and therapeutically targetable vulnerability in imatinib-treated CML patient-derived samples.


Asunto(s)
Leucemia Mielógena Crónica BCR-ABL Positiva , Ácido Pirúvico , Humanos , Mesilato de Imatinib/farmacología , Mesilato de Imatinib/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Aclimatación , Bioensayo
6.
Leukemia ; 35(6): 1539-1551, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-33707653

RESUMEN

Folate-mediated one carbon (1C) metabolism supports a series of processes that are essential for the cell. Through a number of interlinked reactions happening in the cytosol and mitochondria of the cell, folate metabolism contributes to de novo purine and thymidylate synthesis, to the methionine cycle and redox defence. Targeting the folate metabolism gave rise to modern chemotherapy, through the introduction of antifolates to treat paediatric leukaemia. Since then, antifolates, such as methotrexate and pralatrexate have been used to treat a series of blood cancers in clinic. However, traditional antifolates have many deleterious side effects in normal proliferating tissue, highlighting the urgent need for novel strategies to more selectively target 1C metabolism. Notably, mitochondrial 1C enzymes have been shown to be significantly upregulated in various cancers, making them attractive targets for the development of new chemotherapeutic agents. In this article, we present a detailed overview of folate-mediated 1C metabolism, its importance on cellular level and discuss how targeting folate metabolism has been exploited in blood cancers. Additionally, we explore possible therapeutic strategies that could overcome the limitations of traditional antifolates.


Asunto(s)
Antineoplásicos/farmacología , Carbono/metabolismo , Antagonistas del Ácido Fólico/farmacología , Ácido Fólico/metabolismo , Neoplasias Hematológicas/tratamiento farmacológico , Animales , Neoplasias Hematológicas/metabolismo , Neoplasias Hematológicas/patología , Humanos
7.
Sci Transl Med ; 13(613): eabd5016, 2021 Sep 29.
Artículo en Inglés | MEDLINE | ID: mdl-34586834

RESUMEN

Inhibition of autophagy has been proposed as a potential therapy for individuals with cancer. However, current lysosomotropic autophagy inhibitors have demonstrated limited efficacy in clinical trials. Therefore, validation of novel specific autophagy inhibitors using robust preclinical models is critical. In chronic myeloid leukemia (CML), minimal residual disease is maintained by persistent leukemic stem cells (LSCs), which drive tyrosine kinase inhibitor (TKI) resistance and patient relapse. Here, we show that deletion of autophagy-inducing kinase ULK1 (unc-51­like autophagy activating kinase 1) reduces growth of cell line and patient-derived xenografted CML cells in mouse models. Using primitive cells, isolated from individuals with CML, we demonstrate that pharmacological inhibition of ULK1 selectively targets CML LSCs ex vivo and in vivo, when combined with TKI treatment. The enhanced TKI sensitivity after ULK1-mediated autophagy inhibition is driven by increased mitochondrial respiration and loss of quiescence and points to oxidative stress­induced differentiation of CML LSCs, proposing an alternative strategy for treating patients with CML.


Asunto(s)
Autofagia , Estrés Oxidativo , Homólogo de la Proteína 1 Relacionada con la Autofagia/metabolismo , Diferenciación Celular , Células Madre/metabolismo
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