Metabolic Reprogramming and Cell Adhesion in Acute Leukemia Adaptation to the CNS Niche

Sharma, Nitesh; Keewan, Esra’a; Matławska-Wasowska, Ksenia

doi:10.3389/fcell.2021.767510

Cited by 5 publications

(8 citation statements)

References 147 publications

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“…S4G), suggesting their potential as a biomarker for brain in ltration in B-ALL. Previous studies have been extensively reviewed the impact of speci c genetic lesions [44], CNS niche [45], chemokines and cytokines [46,47], growth factors [48], metabolic reprogramming and cell adhesion [49] in driving leukemic cells to the CNS. Although ACSM3 involving in the fatty acid metabolism [50] and HRK playing a pro-apoptotic role by interacting with BCL2 [51] have been reported, the functions on CNS leukemia remains unknown and requires further study.…”

Section: Discussionmentioning

confidence: 99%

Single-cell heterogeneity and dynamic evolution of Ph-like acute lymphoblastic leukemia patient with novel TPR-PDGFRB fusion gene

Zhang

Hou

Huang

et al. 2022

Preprint

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Background Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a refractory and recurrent subtype of B-cell ALL enriched with kinase-activating rearrangements. Incomplete understanding of the heterogeneity within the tumor cells presents a major challenge for the diagnosis and therapy of Ph-like ALL. Methods Single-cell RNA sequencing (scRNA-seq) was performed on 10,273 bone marrow mononuclear cells obtained from one patient with Ph-like ALL at diagnosis and after relapse. Integrative single-cell analysis was performed on this Ph-like ALL patient and two Ph+ ALL patients at diagnosis and relapse from a previous study. Results scRNA-seq analysis exhibited a comprehensive cell atlas of one Ph-like ALL patient with a novel TPR-PDGFRB fusion gene at diagnosis and relapse. Twelve heterogeneous B-cell clusters, four with strong MKI67 expression indicating highly proliferating B cells, were identified. A relapse-enriched B-cell subset associated with poor prognosis was discovered, implicating the transcriptomic evolution during disease progression. Integrative single-cell analysis was performed on Ph-like ALL and Ph+ ALL patients, and revealed Ph-like specific B-cell subpopulations and common CD8+ T cells characterized by the expression of the inhibitory receptor KLRB1. Conclusions Collectively, scRNA-seq of Ph-like ALL with a novel TPR-PDGFRB fusion gene provides valuable insights into the underlying heterogeneity associated with disease progression and offers useful information for the development of immunotherapeutic techniques in the future.

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Section: Discussionmentioning

confidence: 99%

Single-cell heterogeneity and dynamic evolution of Ph-like acute lymphoblastic leukemia patient with novel TPR-PDGFRB fusion gene

Zhang

Hou

Huang

et al. 2022

Preprint

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“…Tumors devote a great part of their energy consumption to growth; therefore, a downregulation of metabolic demand and tissue acidification define the hypoxic parts of a tumor, which is a physiological result of rapid growth and insufficient circulation [ 67 ]. Stimulated by hypoxia, the hypoxia-inducible factor (HIF) can activate transcription factors that target genes involved in tumor microenvironment remodeling, tumorigenesis, and metastasis processes such as metabolism, growth, EMT, angiogenesis, immune evasion, and resistance [ 30 , 53 , 67 , 90 , 93 , 94 , 95 ].…”

Section: Involvement Of Itga6 In Cancer Metastasismentioning

confidence: 99%

“…Otto Warburg was the first to describe tumor cells’ abnormal metabolic function [ 96 , 97 ]. Recent research has found that cancer cell adhesion, which is a key regulator of leukemia growth and chemoresistance, may either induce or be induced by metabolic reprogramming-related cell signaling pathways [ 95 ]. ROS may activate numerous oncogenic pathways (e.g., PI3K/AKT, NF-κB, and p38/MAPK) by stabilizing HIF1 [ 98 ].…”

Section: Involvement Of Itga6 In Cancer Metastasismentioning

confidence: 99%

“…For a long time, it was assumed that leukemia cells entered the CNS through the bloodstream [ 117 ]. However, it has been demonstrated that acute lymphoblastic leukemia cells travel straight from the bone marrow to the CNS surrounds via the laminin-rich ECM of emissary bridging arteries rather than metastasizing within the circulation as in the case of solid tumor cells [ 59 , 73 , 95 , 110 ]. Moreover, the dural lymphatic system provides a new lymphocyte trafficking channel, and acute lymphoblastic leukemia cells use CNS lymphatics to enter or exit the CNS [ 117 ].…”

Section: Involvement Of Itga6 In Cancer Metastasismentioning

confidence: 99%

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Regulation and Functions of α6-Integrin (CD49f) in Cancer Biology

Khademi

Malekzadeh

Bahrami

et al. 2023

Cancers

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Over the past decades, our knowledge of integrins has evolved from being understood as simple cell surface adhesion molecules to receptors that have a complex range of intracellular and extracellular functions, such as delivering chemical and mechanical signals to cells. Consequently, they actively control cellular proliferation, differentiation, and apoptosis. Dysregulation of integrin signaling is a major factor in the development and progression of many tumors. Many reviews have covered the broader integrin family in molecular and cellular studies and its roles in diseases. Nevertheless, further understanding of the mechanisms specific to an individual subunit of different heterodimers is more useful. Thus, we describe the current understanding of and exploratory investigations on the α6-integrin subunit (CD49f, VLA6; encoded by the gene itga6) in normal and cancer cells. The roles of ITGA6 in cell adhesion, stemness, metastasis, angiogenesis, and drug resistance, and as a diagnosis biomarker, are discussed. The role of ITGA6 differs based on several features, such as cell background, cancer type, and post-transcriptional alterations. In addition, exosomal ITGA6 also implies metastatic organotropism. The importance of ITGA6 in the progression of a number of cancers, including hematological malignancies, suggests its potential usage as a novel prognostic or diagnostic marker and useful therapeutic target for better clinical outcomes.

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“…adaption to the CNS microenvironment and contact-induced quiescence. Accumulating evidence supports that the low oxygen and nutrient availability in the CSF induce metabolic adaptations in the leukemic cells that promote their survival in the CNS microenvironment [110]. Several studies have shown that hypoxia-gene expression signatures are upregulated in leukemic cells located in the CNS, and that treatment with the anti-VEGF antibody bevacizumab significantly reduced CNS leukemia in ALL xenograft models [85,111].…”

Section: Novel Drugs That Target Cell Survival Mechanismsmentioning

confidence: 99%

Central nervous system involvement in childhood acute lymphoblastic leukemia: challenges and solutions

et al. 2022

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Delivery of effective anti-leukemic agents to the central nervous system (CNS) is considered essential for cure of childhood acute lymphoblastic leukemia. Current CNS-directed therapy comprises systemic therapy with good CNS-penetration accompanied by repeated intrathecal treatments up to 26 times over 2–3 years. This approach prevents most CNS relapses, but is associated with significant short and long term neurotoxicity. Despite this burdensome therapy, there have been no new drugs licensed for CNS-leukemia since the 1960s, when very limited anti-leukemic agents were available and there was no mechanistic understanding of leukemia survival in the CNS. Another major barrier to improved treatment is that we cannot accurately identify children at risk of CNS relapse, or monitor response to treatment, due to a lack of sensitive biomarkers. A paradigm shift in treating the CNS is needed. The challenges are clear – we cannot measure CNS leukemic load, trials have been unable to establish the most effective CNS treatment regimens, and non-toxic approaches for relapsed, refractory, or intolerant patients are lacking. In this review we discuss these challenges and highlight research advances aiming to provide solutions. Unlocking the potential of risk-adapted non-toxic CNS-directed therapy requires; (1) discovery of robust diagnostic, prognostic and response biomarkers for CNS-leukemia, (2) identification of novel therapeutic targets combined with associated investment in drug development and early-phase trials and (3) engineering of immunotherapies to overcome the unique challenges of the CNS microenvironment. Fortunately, research into CNS-ALL is now making progress in addressing these unmet needs: biomarkers, such as CSF-flow cytometry, are now being tested in prospective trials, novel drugs are being tested in Phase I/II trials, and immunotherapies are increasingly available to patients with CNS relapses. The future is hopeful for improved management of the CNS over the next decade.

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Metabolic Reprogramming and Cell Adhesion in Acute Leukemia Adaptation to the CNS Niche

Cited by 5 publications

References 147 publications

Single-cell heterogeneity and dynamic evolution of Ph-like acute lymphoblastic leukemia patient with novel TPR-PDGFRB fusion gene

Single-cell heterogeneity and dynamic evolution of Ph-like acute lymphoblastic leukemia patient with novel TPR-PDGFRB fusion gene

Regulation and Functions of α6-Integrin (CD49f) in Cancer Biology

Central nervous system involvement in childhood acute lymphoblastic leukemia: challenges and solutions

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