Proliferative Signals in Chronic Lymphocytic Leukemia; What Are We Missing?

Haselager, Marco V.; Kater, Arnon P.; Eldering, Eric

doi:10.3389/fonc.2020.592205

Cited by 44 publications

(49 citation statements)

References 138 publications

(269 reference statements)

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“…Despite the contribution of an increasing number of studies, not only CLL is still incurable but also the underlying pathogenic mechanisms still need to be fully elucidated. In particular, mechanisms orchestrating the trafficking of the leukemic cells between the PB and the lymphoid tissues, where they organize and interact with a supportive microenvironment, have not been fully explained yet ( 6 ). Leukemic cells in the tissues establish a crosstalk with the cells from the microenvironment, which strongly support their survival and proliferation through direct contact and the secretion of specific stimuli ( 7 , 8 ).…”

Section: Introductionmentioning

confidence: 99%

3D Bioprinting Allows the Establishment of Long-Term 3D Culture Model for Chronic Lymphocytic Leukemia Cells

et al. 2021

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Chronic Lymphocytic Leukemia (CLL) represents the most common leukemia in the western world and remains incurable. Leukemic cells organize and interact in the lymphoid tissues, however what actually occurs in these sites has not been fully elucidated yet. Studying primary CLL cells in vitro is very challenging due to their short survival in culture and also to the fact that traditional two-dimensional in vitro models lack cellular and spatial complexity present in vivo. Based on these considerations, we exploited for the first time three-dimensional (3D) bioprinting to advance in vitro models for CLL. This technology allowed us to print CLL cells (both primary cells and cell lines) mixed with the appropriate, deeply characterized, hydrogel to generate a scaffold containing the cells, thus avoiding the direct cell seeding onto a precast 3D scaffold and paving the way to more complex models. Using this system, we were able to efficiently 3D bioprint leukemic cells and improve their viability in vitro that could be maintained up to 28 days. We monitored over time CLL cells viability, phenotype and gene expression, thus establishing a reproducible long-term 3D culture model for leukemia. Through RNA sequencing (RNAseq) analysis, we observed a consistent difference in gene expression profile between 2D and 3D samples, indicating a different behavior of the cells in the two different culture settings. In particular, we identified pathways upregulated in 3D, at both day 7 and 14, associated with immunoglobulins production, pro-inflammatory molecules expression, activation of cytokines/chemokines and cell-cell adhesion pathways, paralleled by a decreased production of proteins involved in DNA replication and cell division, suggesting a strong adaptation of the cells in the 3D culture. Thanks to this innovative approach, we developed a new tool that may help to better mimic the physiological 3D in vivo settings of leukemic cells as well as of immune cells in broader terms. This will allow for a more reliable study of the molecular and cellular interactions occurring in normal and neoplastic conditions in vivo, and could also be exploited for clinical purposes to test individual responses to different drugs.

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Section: Introductionmentioning

confidence: 99%

3D Bioprinting Allows the Establishment of Long-Term 3D Culture Model for Chronic Lymphocytic Leukemia Cells

et al. 2021

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“…For all these reasons, it is very challenging to reproduce in vitro what occurs in vivo possibly leading to CLL cells proliferation. Recently, Haselager et al gave an overview of in vivo versus in vitro signals involved in CLL cells proliferation that we should take into consideration for the development of more complex in vitro models (16).…”

Section: The Tissue Microenvironment In B Cell Malignanciesmentioning

confidence: 99%

“…Describing the components present in the tissue microenvironment is not the focus of this review [recently reviewed by Haselager et al (16)] and we will provide a brief overview on few components that may have more relevance when considering building a functional system in vitro.…”

Section: The Cellular and Molecular Components Of The Tissue Microenvmentioning

confidence: 99%

Modeling the Leukemia Microenviroment In Vitro

Scielzo

Ghia

2020

Front. Oncol.

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Over the last decade, the active role of the microenvironment in the pathogenesis, development and drug resistance of B cell malignancies has been clearly established. It is known that the tissue microenvironment promotes proliferation and drug resistance of leukemic cells suggesting that successful treatments of B cell malignancies must target the leukemic cells within these compartments. However, the cross-talk occurring between cancer cells and the tissue microenvironment still needs to be fully elucidated. In solid tumors, this lack of knowledge has led to the development of new and more complex in vitro models able to successfully mimic the in vivo settings, while only a few simplified models are available for haematological cancers, commonly relying only on the co-culture with stabilized stromal cells and/or the addition of limited cocktails of cytokines. Here, we will review the known cellular and molecular interactions occurring between monoclonal B lymphocytes and their tissue microenvironment and the current literature describing innovative in vitro models developed in particular to study chronic lymphocytic leukemia (CLL). We will also elaborate on the possibility to further improve such systems based on the current knowledge of the key molecules/signals present in the microenvironment. In particular, we think that future models should be developed as 3D culture systems with a higher level of cellular and molecular complexity, to replicate microenvironmental-induced signaling. We believe that innovative 3D-models may therefore improve the knowledge on pathogenic mechanisms leading to the dissemination and homing of leukemia cells and consequently the identification of therapeutic targets.

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“…Leukemia has different subtypes, which are classified in the context of the tumor origin [2]. The most common variety in adults is chronic lymphocytic leukemia (CLL), which is a lymphoid malignancy due to failed apoptosis and aggressive proliferation of mature B cells [3]. These cells circulate through the blood as non-proliferating cells or arrested cells in the G0/G1 phase of the cell cycle and may affect the function of normal cells in other organs [4].…”

Section: Introductionmentioning

confidence: 99%

Identification of LncRNAs as Therapeutic Targets in Chronic Lymphocytic Leukemia

Dolaner

Kaur

Brodsky

et al. 2021

CUSJ

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Chronic Lymphocytic Leukemia (CLL) is one kind of blood cancer that has a very heterogeneous biological background, which results in diverse stages of the CLL and complex treatment strategies. However, a small part of the tumor may disappear without receiving any treatment. This condition is known as “spontaneous regression” and occurs as a result of a poorly investigated mechanism. Exposing the underlying causes of this condition can lead to a novel treatment approach for CLL and other types of cancer. While most such mechanisms have been assumed to be directly linked to protein coding genes, a recent approach was aimed to carry out more comprehensive studies by focusing on non-protein coding genes as well as protein-coding genes at the RNA level. In this article, we applied in-silico analysis of total RNA expression data from 24 CLL samples to determine possible regulatory mechanisms of spontaneous regression in CLL. These were selected by comparing spontaneous regression with progressive samples of CLL at the transcriptional level. As a result, 33 lncRNAs were found to be significantly differentially expressed among these conditions based on differential gene expression analysis. Current study suggested lncRNAs, PTPN22-AS1, PCF11-AS1, SYNGAP1-AS1, PRRT3-AS1 and H1FX-AS1 as potential therapeutic targets to trigger spontaneous regression. Eventually, the results presented here reveal new insights into the spontaneous regression and the relation with the non-coding RNAs, particularly lncRNAs.

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Proliferative Signals in Chronic Lymphocytic Leukemia; What Are We Missing?

Cited by 44 publications

References 138 publications

3D Bioprinting Allows the Establishment of Long-Term 3D Culture Model for Chronic Lymphocytic Leukemia Cells

3D Bioprinting Allows the Establishment of Long-Term 3D Culture Model for Chronic Lymphocytic Leukemia Cells

Modeling the Leukemia Microenviroment In Vitro

Identification of LncRNAs as Therapeutic Targets in Chronic Lymphocytic Leukemia

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