scholarly journals Chromothripsis in Chronic Lymphocytic Leukemia: A Driving Force of Genome Instability

2021 ◽  
Vol 11 ◽  
Author(s):  
Kristyna Zavacka ◽  
Karla Plevova
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Hematological Malignancies ◽  
Genome Instability ◽  
Current Knowledge ◽  
Chromosomal Rearrangements ◽  
Treatment Strategies ◽  
Lymphocytic Leukemia ◽  
Adverse Clinical Outcome ◽  
Molecular Abnormalities ◽  
Cancer Types

Chromothripsis represents a mechanism of massive chromosome shattering and reassembly leading to the formation of derivative chromosomes with abnormal functions and expression. It has been observed in many cancer types, importantly, including chronic lymphocytic leukemia (CLL). Due to the associated chromosomal rearrangements, it has a significant impact on the pathophysiology of the disease. Recent studies have suggested that chromothripsis may be more common than initially inferred, especially in CLL cases with adverse clinical outcome. Here, we review the main features of chromothripsis, the challenges of its assessment, and the potential benefit of its detection. We summarize recent findings of chromothripsis occurrence across hematological malignancies and address its causes and consequences in the context of CLL clinical features, as well as chromothripsis-related molecular abnormalities described in published CLL studies. Furthermore, we discuss the use of the current knowledge about genome functions associated with chromothripsis in the optimization of treatment strategies in CLL.

scholarly journals COMPARISON OF CHROMOSOMAL REARRANGEMENTS IN BONE MARROW CELLS AND BLAST TRANSFORMED B-CELLS IN RELAPSE OF B-CELL CHRONIC LYMPHOCYTIC LEUKEMIA/ SMALL LYMPHOCYTIC LYMPHOMA

2017 ◽  
Vol 39 (2) ◽  
pp. 141-144
Author(s):  
S V Andreieva ◽  
K V Korets ◽  
O E Ruzhinska ◽  
I M Skorokhod ◽  
O G Alkhimova
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Chromosomal Rearrangements ◽  
Lymphocytic Leukemia ◽  
Banding Technique ◽  
Small Lymphocytic Lymphoma ◽  
Detection Frequency ◽  
Cell Chronic Lymphocytic Leukemia

Aim: The genetic mechanisms of resistance to chemotherapy in B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma (B-CLL/SLL) are not clear. We aimed to determine the peculiarities of abnormal karyotype formation in bone marrow (BM) cells and peripheral blood (PB) blast transformed B-cells in relapse of B-CLL/SLL. Materials and Methods: Cytogenetic GTG banding technique and molecular cytogenetic in interphase cells (i-FISH) studies of BM cells and PB blast transformed B-lymphocytes were performed in 14 patients (10 males and 4 females) with B-CLL/SLL. Results: The results of karyotyping BM and PB cells revealed the heterogeneity of cytogenetic abnormalities in combined single nosological group of B-CLL/SLL. In PB B-cells, chromosome abnormalities related to a poor prognosis group were registered 2.5 times more often than in BM cells. Additional near tetraploid clones that occurred in 57.1% cases were the peculiar feature of BM cell karyotypes. Chromosomal rearrangements characteristic of the group of adverse cytogenetic prognosis were revealed in all cases from which in 2 cases by karyotyping BM cells, in 6 cases in PB B-cells and in 8 cases by the i-FISH method in BM cells, i.e. their detection frequency was 3 times higher in PB B-cells and 4 times higher when analyzing by i-FISH in BM cells. Conclusions: Mismatch in abnormal karyotypes in BM and PB B-cells by the presence of quantitative and structural chromosomal rearrangements may be indicative of simultaneous and independent processes of abnormal clone formation in the lymph nodes and BM hematopoietic cells. Accumulation the information about previously unidentified chromosomal rearrangements in relapse of the disease may help to understand the ways of resistance formation to chemotherapy.

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.

scholarly journals Trends in the risk of second primary malignancies among survivors of chronic lymphocytic leukemia

2019 ◽  
Vol 9 (10) ◽  
Author(s):  
Vivek Kumar ◽  
Sikander Ailawadhi ◽  
Leyla Bojanini ◽  
Aditya Mehta ◽  
Suman Biswas ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Hematological Malignancies ◽  
Lymphocytic Leukemia ◽  
Second Primary ◽  
Standardized Incidence Ratio ◽  
Improved Outcomes ◽  
History Of ◽  
Second Primary Malignancies

Abstract With improving survivorship in chronic lymphocytic leukemia (CLL), the risk of second primary malignancies (SPMs) has not been systematically addressed. Differences in risk for SPMs among CLL survivors from the Surveillance, Epidemiology, and End Results (SEER) database (1973–2015) were compared to risk of individual malignancies expected in the general population. In ~270,000 person-year follow-up, 6487 new SPMs were diagnosed with a standardized incidence ratio (SIR) of 1.2 (95% CI:1.17–1.23). The higher risk was for both solid (SIR 1.15; 95% CI:1.12–1.18) and hematological malignancies (SIR 1.61; 95% CI:1.5–1.73). The highest risk for SPMs was noted between 2 and 5 months after CLL diagnosis (SIR 1.57; 95% CI:1.41–1.74) and for CLL patients between 50- and 79-years-old. There was a significant increase in SPMs in years 2003–2015 (SIR 1.36; 95% CI:1.3–1.42) as compared to 1973–1982 (SIR 1.19; 95% CI:1.12–1.26). The risk of SPMs was higher in CLL patients who had received prior chemotherapy (SIR 1.38 95% CI:1.31–1.44) as compared to those untreated/treatment status unknown (SIR 1.16, 95% CI:1.13–1.19, p < 0.001). In a multivariate analysis, the hazard of developing SPMs was higher among men, post-chemotherapy, recent years of diagnosis, advanced age, and non-Whites. Active survivorship plans and long-term surveillance for SPMs is crucial for improved outcomes of patients with a history of CLL.

Angiopoietin-2 Expression in B-Cell Chronic Lymphocytic Leukemia: Association with Clinical Outcome and Immunoglobulin Heavy-Chain Mutational Status.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2780-2780
Author(s):  
Rossana Maffei ◽  
Silvia Martinelli ◽  
Ilaria Castelli ◽  
Rita Santachiara ◽  
Elena Morandi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Chronic Lymphocytic Leukemia ◽  
Clinical Outcome ◽  
Heavy Chain ◽  
Lymphocytic Leukemia ◽  
Adverse Clinical Outcome ◽  
Mutational Status ◽  
Angiopoietin 2 ◽  
Normal Controls ◽  
Cell Chronic Lymphocytic Leukemia

Abstract B-cell Chronic Lymphocytic Leukemia (B-CLL) follows an extremely variable clinical course. For some patients CLL is an indolent disease that never progresses to the point of requiring therapy and these patients have a survival time similar to age-matched controls. On the contrary, other patients experience rapidly deteriorating blood count and organomegaly which requires prompt treatment. The overall survival (OS) times range from months to decades. B-CLL patients can be divided into two subgroups on the basis of the presence or absence of somatic mutations in the specific immunoglobulin heavy-chain variable region (IgVH) genes used by leukemic cells. Patients with unmutated IgVH genes usually have an advanced stage and an unfavourable cytogenetic features, require therapy and have a short survival. The biological reasons of the different behaviour of Ig-mutated and Ig-unmutated leukemic clones have not been fully elucidated yet. Angiogenesis is a very complex network which is closely regulated by the orchestrating functions of many angiogenic factors. The balance of cellular expression of all these angiogenic factors determines vascular stabilization or angiogenic remodelling and sprouting or vessel regression. Increasing evidence shows that neovascularization plays a role in the biology of chronic lymphocytic leukemia. The goal of this study was to evaluate the angiogenic status of Ig-mutated and Ig-unmutated CLL in the attempt to identify a possible role of angiogenesis in the adverse clinical outcome of Ig-unmutated CLL patients. So, we first performed a large scale gene-expression analysis on 29 B-CLL patients using microarrays comprising about 20,000 probes and 208 angiogenesis-related genes. We identified 64 up-regulated genes in Ig-unmutated CLL relative to Ig-mutated CLL. Among them, we found angiopoietin-2 (Ang-2) as one of the highest differentially expressed gene (p=3.02x10−6). Then, we evaluated the Ang-2 expression both at transcript and protein level in a wide cohort of CLL, in normal controls and in other haematological malignancies. The data showed an extremely wide range of Ang-2 expression in B-CLL: Ang-2 high-expressing cases were characterized by advanced Binet stage (p=0.032) and significantly shorter progression-free survival than Ang-2 low-expressing subset (median, 16 vs. 146 months) (p=0.006). Moreover, there was a strong correlation between the IgVH mutational status and the Ang-2 gene expression level (p<0.0001). Ig-mutated CLL exhibited very low Ang-2 expression, absolutely similar to the levels measured in healthy controls (median, 0.27 vs. 0.32, p=0.959). On the contrary, Ig-unmutated CLL expressed up to one hundred-fold higher levels of Ang-2 than normal controls(median, 38.61 vs. 0.32, p=0.002). Moreover, Ang-2 was up-regulated in all investigated CML, ALL and AML samples. We observed extremely high levels of expression in CML and ALL (median Ang-2 mRNA, 3948.96 and 190.00, respectively), whereas moderately high levels of Ang-2 were found in AML patients (median, 16.21). These data suggest that increased angiogenesis due to high Ang-2 expression may be involved in adverse clinical outcome of Ig-unmutated CLL patients.

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.

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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