Leukemic Stem Cells: From Leukemic Niche Biology to Treatment Opportunities

Marchand, Tony; Pinho, Sandra

doi:10.3389/fimmu.2021.775128

Cited by 46 publications

(36 citation statements)

References 166 publications

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“…NF-κB plays a pivotal role also in LSCs, where it regulates survival, proliferation and chemoresistance [ 28 ]. Zhou and collaborators demonstrated that NF-κB fosters stem-like properties (i.e., self-renewal capacity) of AML cells via LIN28B activation.…”

Section: Nf-κb Pathway In Aml Pathogenesismentioning

confidence: 99%

NF-κB: A Druggable Target in Acute Myeloid Leukemia

Francesco

Verzella

Capece

et al. 2022

Cancers

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Acute Myeloid Leukemia (AML) is an aggressive hematological malignancy that relies on highly heterogeneous cytogenetic alterations. Although in the last few years new agents have been developed for AML treatment, the overall survival prospects for AML patients are still gloomy and new therapeutic options are still urgently needed. Constitutive NF-κB activation has been reported in around 40% of AML patients, where it sustains AML cell survival and chemoresistance. Given the central role of NF-κB in AML, targeting the NF-κB pathway represents an attractive strategy to treat AML. This review focuses on current knowledge of NF-κB’s roles in AML pathogenesis and summarizes the main therapeutic approaches used to treat NF-κB-driven AML.

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Section: Nf-κb Pathway In Aml Pathogenesismentioning

confidence: 99%

NF-κB: A Druggable Target in Acute Myeloid Leukemia

Francesco

Verzella

Capece

et al. 2022

Cancers

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“…In this scenario, research diverges in different areas such as transport proteins and signaling pathways, taking as an example Notch, Hedgehog, and Wnt/b-catenin that are describes also as responsible for drug resistance (104,(127)(128)(129). It is also worth mentioning studies focused on the epithelial-mesenchymal transition (EMT), histone acetylation, hypoxia and the BM niche (104,130,131).…”

Section: Treatment Perspectivesmentioning

confidence: 99%

Leukemic Stem Cell: A Mini-Review on Clinical Perspectives

Barreto

Pessoa²,

Machado³

et al. 2022

Front. Oncol.

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Hematopoietic stem cells (HSCs) are known for their ability to proliferate and self-renew, thus being responsible for sustaining the hematopoietic system and residing in the bone marrow (BM). Leukemic stem cells (LSCs) are recognized by their stemness features such as drug resistance, self-renewal, and undifferentiated state. LSCs are also present in BM, being found in only 0.1%, approximately. This makes their identification and even their differentiation difficult since, despite the mutations, they are cells that still have many similarities with HSCs. Although the common characteristics, LSCs are heterogeneous cells and have different phenotypic characteristics, genetic mutations, and metabolic alterations. This whole set of alterations enables the cell to initiate the process of carcinogenesis, in addition to conferring drug resistance and providing relapses. The study of LSCs has been evolving and its application can help patients, where through its count as a biomarker, it can indicate a prognostic factor and reveal treatment results. The selection of a target to LSC therapy is fundamental. Ideally, the target chosen should be highly expressed by LSCs, highly selective, absence of expression on other cells, in particular HSC, and preferentially expressed by high numbers of patients. In view of the large number of similarities between LSCs and HSCs, it is not surprising that current treatment approaches are limited. In this mini review we seek to describe the immunophenotypic characteristics and mechanisms of resistance presented by LSCs, also approaching possible alternatives for the treatment of patients.

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“…Leukemic stem cells (LSCs) are multipotent, proliferative, and self-renewing cells that propagate leukemia ( 210 ). In AML LSCs, oxysterol-binding protein-related protein 4L (ORP4L) acts as a scaffold protein that facilitates PIP2 presentation to PLC-β3 for cleavage into IP3 ( 211 ).…”

Section: Calcium Signaling Deregulation In Blood Cancermentioning

confidence: 99%

Deregulated calcium signaling in blood cancer: Underlying mechanisms and therapeutic potential

Immanuel

Li²,

Green³

et al. 2022

Front. Oncol.

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Intracellular calcium signaling regulates diverse physiological and pathological processes. In solid tumors, changes to calcium channels and effectors via mutations or changes in expression affect all cancer hallmarks. Such changes often disrupt transport of calcium ions (Ca2+) in the endoplasmic reticulum (ER) or mitochondria, impacting apoptosis. Evidence rapidly accumulates that this is similar in blood cancer. Principles of intracellular Ca2+ signaling are outlined in the introduction. We describe different Ca2+-toolkit components and summarize the unique relationship between extracellular Ca2+ in the endosteal niche and hematopoietic stem cells. The foundational data on Ca2+ homeostasis in red blood cells is discussed, with the demonstration of changes in red blood cell disorders. This leads to the role of Ca2+ in neoplastic erythropoiesis. Then we expand onto the neoplastic impact of deregulated plasma membrane Ca2+ channels, ER Ca2+ channels, Ca2+ pumps and exchangers, as well as Ca2+ sensor and effector proteins across all types of hematologic neoplasms. This includes an overview of genetic variants in the Ca2+-toolkit encoding genes in lymphoid and myeloid cancers as recorded in publically available cancer databases. The data we compiled demonstrate that multiple Ca2+ homeostatic mechanisms and Ca2+ responsive pathways are altered in hematologic cancers. Some of these alterations may have genetic basis but this requires further investigation. Most changes in the Ca2+-toolkit do not appear to define/associate with specific disease entities but may influence disease grade, prognosis, treatment response, and certain complications. Further elucidation of the underlying mechanisms may lead to novel treatments, with the aim to tailor drugs to different patterns of deregulation. To our knowledge this is the first review of its type in the published literature. We hope that the evidence we compiled increases awareness of the calcium signaling deregulation in hematologic neoplasms and triggers more clinical studies to help advance this field.

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Leukemic Stem Cells: From Leukemic Niche Biology to Treatment Opportunities

Cited by 46 publications

References 166 publications

NF-κB: A Druggable Target in Acute Myeloid Leukemia

NF-κB: A Druggable Target in Acute Myeloid Leukemia

Leukemic Stem Cell: A Mini-Review on Clinical Perspectives

Deregulated calcium signaling in blood cancer: Underlying mechanisms and therapeutic potential

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