Leukemia stem cell immunophenotyping tool for diagnostic, prognosis, and therapeutics

Rezende, Marina Mastelaro de; Ferreira, Alice Teixeira; Paredes‐Gamero, Edgar Julian

doi:10.1002/jcp.29394

Cited by 8 publications

(5 citation statements)

References 50 publications

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“…Leukemia stem cell (LSC) is considered to be responsible for the initiation, maintenance, chemotherapy resistance, and relapse of AML. In addition, LSC is hard to be completely eradicated by therapeutic strategies, including chemotherapy, BMT, and radiotherapy 6 . However, LSC has some similarities with normal HSPC.…”

Section: Introductionmentioning

confidence: 99%

DNA hypermethylation-induced miR-182 silence targets BCL2 and HOXA9 to facilitate the self-renewal of leukemia stem cell, accelerate acute myeloid leukemia progression, and determine the sensitivity of BCL2 inhibitor venetoclax

Ye¹,

Xiong²,

He³

et al. 2023

Theranostics

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Rationale: microRNAs (miRNAs) are frequently deregulated and play important roles in the pathogenesis and progression of acute myeloid leukemia (AML). miR-182 functions as an onco-miRNA or tumor suppressor miRNA in the context of different cancers. However, whether miR-182 affects the self-renewal of leukemia stem cells (LSCs) and normal hematopoietic stem progenitor cells (HSPCs) is unknown. Methods: Bisulfite sequencing was used to analyze the methylation status at pri-miR-182 promoter. Lineage-negative HSPCs were isolated from miR-182 knockout (182KO) and wild-type (182WT) mice to construct MLL-AF9-transformed AML model. The effects of miR-182 depletion on the overall survival and function of LSC were analyzed in this mouse model in vivo. Results: miR-182-5p (miR-182) expression was lower in AML blasts than normal controls (NCs) with hypermethylation observed at putative pri-miR-182 promoter in AML blasts but unmethylation in NCs. Overexpression of miR-182 inhibited proliferation, reduced colony formation, and induced apoptosis in leukemic cells. In addition, depletion of miR-182 accelerated the development and shortened the overall survival (OS) in MLL-AF9-transformed murine AML through increasing LSC frequency and self-renewal ability. Consistently, overexpression of miR-182 attenuated AML development and extended the OS in the murine AML model. Most importantly, miR-182 was likely dispensable for normal hematopoiesis. Mechanistically, we identified BCL2 and HOXA9 as two key targets of miR-182 in this context. Most importantly, AML patients with miR-182 unmethylation had high expression of miR-182 followed by low protein expression of BCL2 and resistance to BCL2 inhibitor venetoclax (Ven) in vitro. Conclusions: Our results suggest that miR-182 is a potential therapeutic target for AML patients through attenuating the self-renewal of LSC but not HSPC. miR-182 promoter methylation could determine the sensitivity of Ven treatment and provide a potential biomarker for it.

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Section: Introductionmentioning

confidence: 99%

DNA hypermethylation-induced miR-182 silence targets BCL2 and HOXA9 to facilitate the self-renewal of leukemia stem cell, accelerate acute myeloid leukemia progression, and determine the sensitivity of BCL2 inhibitor venetoclax

Ye¹,

Xiong²,

He³

et al. 2023

Theranostics

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“…[ 125 ]. The identification of the main features of LSCs may improve diagnosis and treatment [ 126 ]. Naldini et al [ 127 ] discriminated LSCs from regenerating hematopoietic cells and assessed their longitudinal response to chemotherapy by detecting nucleophosmin 1 ( NPM1 ) mutation or chromosomal monosomy by single-cell transcriptomic analyses.…”

Section: Applications Of Scrna-seq In Human Cancer Biologymentioning

confidence: 99%

Advances in single-cell RNA sequencing and its applications in cancer research

Huang,

Ma,

et al. 2023

J Hematol Oncol

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Cancers are a group of heterogeneous diseases characterized by the acquisition of functional capabilities during the transition from a normal to a neoplastic state. Powerful experimental and computational tools can be applied to elucidate the mechanisms of occurrence, progression, metastasis, and drug resistance; however, challenges remain. Bulk RNA sequencing techniques only reflect the average gene expression in a sample, making it difficult to understand tumor heterogeneity and the tumor microenvironment. The emergence and development of single-cell RNA sequencing (scRNA-seq) technologies have provided opportunities to understand subtle changes in tumor biology by identifying distinct cell subpopulations, dissecting the tumor microenvironment, and characterizing cellular genomic mutations. Recently, scRNA-seq technology has been increasingly used in cancer studies to explore tumor heterogeneity and the tumor microenvironment, which has increased the understanding of tumorigenesis and evolution. This review summarizes the basic processes and development of scRNA-seq technologies and their increasing applications in cancer research and clinical practice.

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“…A major challenge in studying LSCs is identifying a possible unique cell surface antigen phenotype, from which it would be possible to develop a targeted and much more specific treatment than the treatments currently used. Furthermore, due to the heterogeneity of the different types of leukemias, there is a lot of variation in the antigens found on the surface of these cells, becoming even more difficult to identify a specific marker that is not expressed in normal cells, or has a different expression pattern, density, or distribution (51)(52)(53)(54).…”

Section: Characterization Of Leukemic Stem Cellsmentioning

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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Leukemia stem cell immunophenotyping tool for diagnostic, prognosis, and therapeutics

Cited by 8 publications

References 50 publications

DNA hypermethylation-induced miR-182 silence targets BCL2 and HOXA9 to facilitate the self-renewal of leukemia stem cell, accelerate acute myeloid leukemia progression, and determine the sensitivity of BCL2 inhibitor venetoclax

DNA hypermethylation-induced miR-182 silence targets BCL2 and HOXA9 to facilitate the self-renewal of leukemia stem cell, accelerate acute myeloid leukemia progression, and determine the sensitivity of BCL2 inhibitor venetoclax

Advances in single-cell RNA sequencing and its applications in cancer research

Leukemic Stem Cell: A Mini-Review on Clinical Perspectives

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