scholarly journals Identification of LncRNAs as Therapeutic Targets in Chronic Lymphocytic Leukemia

2021 ◽  
Vol 15 ◽  
pp. 16-29
Author(s):  
Simay Dolaner ◽  
Harpreet Kaur ◽  
Elia Brodsky ◽  
Julia Panov ◽  
Mohit Mazumder
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Spontaneous Regression ◽  
Therapeutic Targets ◽  
Treatment Strategies ◽  
In Silico Analysis ◽  
Lymphocytic Leukemia ◽  
Transcriptional Level ◽  
Protein Coding ◽  
Protein Coding Genes ◽  
Recent Approach

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.

scholarly journals Chronic lymphocytic leukemia: interplay between noncoding RNAs and protein-coding genes

Blood ◽  
2009 ◽  
Vol 114 (23) ◽  
pp. 4761-4770 ◽  
Author(s):  
George A. Calin ◽  
Carlo M. Croce
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Noncoding Rnas ◽  
Malignant Potential ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Cancer Genes ◽  
New Paradigm ◽  
Protein Coding ◽  
Protein Coding Genes ◽  
Molecular Oncology

Abstract One of the most unexpected and fascinating discoveries in oncology over the past few years is the interplay between abnormalities in protein-coding genes and noncoding RNAs (ncRNAs) that is causally involved in cancer initiation, progression, and dissemination. MicroRNAs (miRNAs), small regulatory ncRNAs, are involved in the pathogenesis of all types of human cancers, including leukemias, mainly via dysregulation of expression of cancer genes. Increasing evidence shows that miRNAs can work as tumor suppressors (inhibiting malignant potential) or oncogenes (activating malignant potential). Researchers first identified this new paradigm of molecular oncology in patients with chronic lymphocytic leukemia (CLL). Understanding the roles of miRNAs and other ncRNAs in leukemic cells is not only uncovering a new layer of gene regulation but also providing new markers for improved diagnosis and prognosis, as well as novel therapeutic options for CLL patients. Herein we focus on the roles of miRNAs and ultraconserved ncRNA genes in CLL, highlighting what is already known about their function, proposing a novel model of CLL predisposition and progression, and describing the challenges for the near future.

scholarly journals Therapeutic Targets in Chronic Lymphocytic Leukemia

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3259
Author(s):  
Luca Laurenti ◽  
Dimitar G. Efremov
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Therapeutic Targets ◽  
Common Type ◽  
Lymphocytic Leukemia ◽  
Western Countries ◽  
B Cell Malignancy ◽  
Adult Leukemia ◽  
Cell Malignancy

Chronic lymphocytic leukemia (CLL) is a common B cell malignancy and is the most common type of adult leukemia in western countries [...]

scholarly journals Spontaneous regression of Merkel cell carcinoma in a patient with chronic lymphocytic leukemia: a case report

2009 ◽  
Vol 3 (1) ◽  
Author(s):  
Tamara Turk ◽  
Zeljka Crncevic Orlic ◽  
Ivana Smoljan ◽  
Antica Nacinovic ◽  
Irena Seili Bekafigo ◽  
...  
Keyword(s):  
Case Report ◽  
Chronic Lymphocytic Leukemia ◽  
Cell Carcinoma ◽  
Merkel Cell Carcinoma ◽  
Spontaneous Regression ◽  
Lymphocytic Leukemia ◽  
Merkel Cell

scholarly journals Phosphoinositide 3-Kinase Signaling in the Tumor Microenvironment: What Do We Need to Consider When Treating Chronic Lymphocytic Leukemia With PI3K Inhibitors?

2021 ◽  
Vol 11 ◽  
Author(s):  
Ebru Aydin ◽  
Sebastian Faehling ◽  
Mariam Saleh ◽  
Laura Llaó Cid ◽  
Martina Seiffert ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Treatment Strategies ◽  
Cell Receptor ◽  
Pi3k Pathway ◽  
Lymphocytic Leukemia ◽  
Pi3k Signaling ◽  
Extracellular Signals ◽  
Pi3k Inhibition

Phosphoinositide 3-kinases (PI3Ks) and their downstream proteins constitute a signaling pathway that is involved in both normal cell growth and malignant transformation of cells. Under physiological conditions, PI3K signaling regulates various cellular functions such as apoptosis, survival, proliferation, and growth, depending on the extracellular signals. A deterioration of these extracellular signals caused by mutational damage in oncogenes or growth factor receptors may result in hyperactivation of this signaling cascade, which is recognized as a hallmark of cancer. Although higher activation of PI3K pathway is common in many types of cancer, it has been therapeutically targeted for the first time in chronic lymphocytic leukemia (CLL), demonstrating its significance in B-cell receptor (BCR) signaling and malignant B-cell expansion. The biological activity of the PI3K pathway is not only limited to cancer cells but is also crucial for many components of the tumor microenvironment, as PI3K signaling regulates cytokine responses, and ensures the development and function of immune cells. Therefore, the success or failure of the PI3K inhibition is strongly related to microenvironmental stimuli. In this review, we outline the impacts of PI3K inhibition on the tumor microenvironment with a specific focus on CLL. Acknowledging the effects of PI3K inhibitor-based therapies on the tumor microenvironment in CLL can serve as a rationale for improved drug development, explain treatment-associated adverse events, and suggest novel combinatory treatment strategies in CLL.

Signaling the end of chronic lymphocytic leukemia: new frontline treatment strategies

Blood ◽  
2013 ◽  
Vol 122 (23) ◽  
pp. 3723-3734 ◽  
Author(s):  
Michael Hallek
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Genetic Parameters ◽  
Treatment Strategies ◽  
Lymphocytic Leukemia ◽  
New Drugs ◽  
The Novel ◽  
Frontline Treatment ◽  
Therapeutic Tools ◽  
The Right ◽  
Near Future

AbstractThe management of chronic lymphocytic leukemia (CLL) is undergoing profound changes. Several new drugs have been approved for CLL treatment (fludarabine, bendamustine, and the monoclonal antibodies alemtuzumab, rituximab, and ofatumumab) and many more drugs are in advanced clinical development to be approved for this disease. In addition, the extreme heterogeneity of the clinical course and our improved ability to foresee the prognosis of this leukemia by the use of clinical, biological, and genetic parameters now allow us to characterize patients with a very mild onset and course, an intermediate prognosis, or a very aggressive course with high-risk leukemia. Therefore, it becomes increasingly challenging to select the right treatment strategy for each condition. This article summarizes the currently available diagnostic and therapeutic tools and gives an integrated recommendation of how to manage CLL in 2013. Moreover, I propose a strategy how we might integrate the novel agents for CLL therapy into sequential treatment approaches in the near future.

ROS-Mediated Upregulation of Noxa Overcomes Drug-Resistance Due to P53-Dysfunction in Chronic Lymphocytic Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2382-2382
Author(s):  
Sanne H. Tonino ◽  
Jacoline M van Laar ◽  
Marinus H. J. van Oers ◽  
Jean Y.J. Wang ◽  
Eric Eldering ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Cell Death ◽  
Chronic Lymphocytic Leukemia ◽  
Combination Treatment ◽  
Conflicts Of Interest ◽  
Alkylating Agents ◽  
Single Agent ◽  
Treatment Strategies ◽  
Cd40 Ligand ◽  
Lymphocytic Leukemia

Abstract Abstract 2382 Poster Board II-359 Although recent advances in treatment-strategies for chronic lymphocytic leukemia (CLL) have resulted in increased remission rates and response duration, the disease eventually relapses, which necessitates repeated cycles of therapy. Eventually most patients develop chemo-resistant disease which infers a very poor prognosis. The activity of purine-analogs and alkylating agents, the backbone of current treatment regimens, depends on functional p53 and chemo-resistance is highly associated with a dysfunctional p53-response. P53-independent sensitization of CLL cells to these compounds could represent a novel strategy to overcome chemo-resistance. Platinum-based compounds have been successfully applied in relapsed lymphoma and recently also in high-risk CLL. In various cancer-types, the activity of such compounds has been found to be p53-independent and in part mediated by p73. In this study we investigated the efficacy and mechanism of action of platinum-based compounds in chemo-refractory CLL. Neither cisplatinum nor oxaliplatin as a single agent induced cell death in clinically relevant doses. However, independent of p53-functional status, platinum-based compounds acted synergistically with fludarabine, which was found to be caspase-dependent. Combination-treatment resulted in strong upregulation of the pro-apoptotic BH3-only protein Noxa. We did not find evidence for a role of p73; however, the observed synergy was found to involve generation of reactive oxygen species (ROS). Co-treatment with ROS-scavengers completely abrogated Noxa-upregulation and cell-death upon combination treatment in p53-dysfunctional CLL. Noxa RNA-interference markedly decreased sensitivity to combination treatment, supporting a key role for Noxa as mediator between ROS signaling and apoptosis induction. In addition to these findings, we tested the effects of platinum-based compounds and fludarabine on drug-resistance resulting from CD40-ligand stimulation of CLL cells, which represents a model for CLL cells in the protective micro-environment of the secondary lymph node-tissue (Hallaert et al Blood 2008 112(13):5141). Combination treatment could overcome CD40-ligand induced chemo-resistance and was, at least in part, mediated by the generation of ROS and marked induction of expression of Noxa. Our data indicate that interference with the cellular redox-balance represents an interesting target to overcome drug resistance due to both p53-dysfunction as well as micro-environmental protective stimuli in CLL. Disclosures: No relevant conflicts of interest to declare.

scholarly journals The Aurora A and B kinases are up-regulated in bone marrow-derived chronic lymphocytic leukemia cells and represent potential therapeutic targets

Haematologica ◽  
2012 ◽  
Vol 97 (8) ◽  
pp. 1246-1254 ◽  
Author(s):  
F. de Paula Careta ◽  
S. Gobessi ◽  
R. A. Panepucci ◽  
E. Bojnik ◽  
F. Morato de Oliveira ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Lymphocytic Leukemia ◽  
Therapeutic Targets ◽  
Lymphocytic Leukemia ◽  
Leukemia Cells ◽  
Aurora A

Allotransplantation for chronic lymphocytic leukemia

Hematology ◽  
2009 ◽  
Vol 2009 (1) ◽  
pp. 602-609 ◽  
Author(s):  
Peter Dreger
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Immune Modulation ◽  
Residual Disease ◽  
Treatment Strategies ◽  
Treatment Resistance ◽  
Lymphocytic Leukemia ◽  
Successful Outcome ◽  
Mortality And Morbidity ◽  
Poor Risk ◽  
Leukemic Clone

AbstractEfforts to develop curative treatment strategies for chronic lymphocytic leukemia (CLL) in recent years have focused on allogeneic stem cell transplantation (alloSCT). The crucial anti-leukemic principle of alloSCT in CLL appears to be the immune-mediated anti-host activities conferred with the graft (graft-versus-leukemia effects, GVL). Evidence for GVL in CLL is provided by studies analyzing the kinetics of minimal residual disease on response to immune modulation after transplantation, suggesting that GVL can result in complete and durable suppression of the leukemic clone. AlloSCT from matched related or unrelated donors can overcome the treatment resistance of poor-risk CLL, ie, purine analogue refractory disease and CLL with del 17p-. Even with reduced-intensity conditioning, alloSCT in CLL is associated with significant mortality and morbidity due to graft-versus-host disease, which has to be weighed against the risk of the disease when defining the indication for transplantation. Therefore, it can be regarded as a reasonable treatment option only for eligible patients who fulfill accepted criteria for poor-risk disease. If alloSCT is considered, it should be performed before CLL has advanced to a status of complete refractoriness to assure an optimum chance for a successful outcome. Prospective trials are underway to prove whether allo-SCT can indeed change the natural history of poor-risk CLL.

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