Accumulation of DNA damage and alteration of the DNA damage response in monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia

Popp, Henning D.; Flach, Johanna; Brendel, Susanne; Ruppenthal, Sabrina; Kleiner, Helga; Seifarth, Wolfgang; Schneider, Sven; Schulze, Torsten J.; Weiß, Christel; Wenz, Frederik; Hofmann, Wolf‐Karsten; Fabarius, Alice

doi:10.1080/10428194.2018.1498494

Cited by 10 publications

(10 citation statements)

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“…Accumulation of DNA damages and error-prone DNA repair are critical features of genetic instability that are believed to be involved in the pathogenesis of CLL [ 43 ]. Although the role of ATM in signaling to repair proteins is associated with a function that could result in resistance mechanism against the alkylating agents, unexpectedly, the loss of ATM protein is consistent with a poor prognosis and aggressive disease in CLL.…”

Section: Introductionmentioning

confidence: 99%

Involvement of classic and alternative non-homologous end joining pathways in hematologic malignancies: targeting strategies for treatment

et al. 2021

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Chromosomal translocations are the main etiological factor of hematologic malignancies. These translocations are generally the consequence of aberrant DNA double-strand break (DSB) repair. DSBs arise either exogenously or endogenously in cells and are repaired by major pathways, including non-homologous end-joining (NHEJ), homologous recombination (HR), and other minor pathways such as alternative end-joining (A-EJ). Therefore, defective NHEJ, HR, or A-EJ pathways force hematopoietic cells toward tumorigenesis. As some components of these repair pathways are overactivated in various tumor entities, targeting these pathways in cancer cells can sensitize them, especially resistant clones, to radiation or chemotherapy agents. However, targeted therapy-based studies are currently underway in this area, and furtherly there are some biological pitfalls, clinical issues, and limitations related to these targeted therapies, which need to be considered. This review aimed to investigate the alteration of DNA repair elements of C-NHEJ and A-EJ in hematologic malignancies and evaluate the potential targeted therapies against these pathways.

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Section: Introductionmentioning

confidence: 99%

Involvement of classic and alternative non-homologous end joining pathways in hematologic malignancies: targeting strategies for treatment

et al. 2021

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“…We hypothesized that LSR in CLL could be due to similar inaccurate DSB repair related to increased proliferation rate and genetic instability. Indeed, CLL is known to harbor DNA repair alterations and to accumulate of DSB across the genome [3][4][5] . This AID independent IgH locus recombination would explain why IgHV and PIM1 mutation rate was low in LSR High CLLs.…”

Section: • Discussionmentioning

confidence: 99%

Increased frequencies of IgH locus suicide recombination points on Chronic Lymphocytic Leukemia with low rate of AID related somatic mutations, cMYC overexpression and short telomeres

Jamal

Parquet

Boutouil

et al. 2022

Preprint

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In normal activated B-cells, Activation Induced-cytidine deaminase (AID) is absolutely required for immunoglobulin (Ig) class switch recombination (CSR) and IGHV somatic hypermutation (SHM). AID is also implicated in the Locus Suicide Recombination (LSR) of the Ig heavy (IgH) locus, resulting in the deletion of the IgH constant part. Chronic lymphocytic leukemia (CLL) is an indolent non-Hodgkin B-cell lymphoma characterized by tumor CLL B-cells that weakly express a B cell receptor (BCR) on their surface. The great majority of CLL tumor B-cells are non class-switched. Searching for abnormalities of IgH locus recombination in CLL, we investigated CSR and LSR in samples from CLL patients (N=47) with high blood tumor cell infiltration (>98%) and in healthy volunteers (HV) as controls (N=9). LSR was detectable at comparable levels in both HV and CLL groups. CSR counts were decreased in CLL samples as expected. As distribution of LSR counts was bimodal, we separated CLL patients in two groups so called LSRHigh and LSRLow. LSRHigh CLLs exhibited very weak AID expression and low mutation rate of IgHV region and of the AID off-target PIM1 gene. LSR junction diversity, evaluated using the Shannon index, was increased in LSRHigh CLLs suggesting that LSR was on-going in these cells. Also, shorter telomeres were observed in LSRHigh CLLs suggesting an increased number of past mitosis. Consistently, increased levels of cMYC expression were detected in LSRHigh CLLs and treatment free survival of these cases was markedly decreased. We hypothesized that LSR in LSRHigh CLLs is AID independent and could be due to DNA lesion and inaccurate DSB repair within the IgH locus which could be accessible to recombination machinery due to increased IgH locus transcription. Altogether, our results indicate the accessibility of IgH locus and the proliferation increase LSR rate in LSRHigh CLLs could be related to cMYC resulting in shorter treatment free survival of patients and point on an AID independent mechanism of IgH recombination.

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“…The common genetic abnormalities (Rawstron et al 2008;Shanafelt et al 2009a;Molica et al 2011) and susceptibility loci (Crowther-Swanepoel et al 2010b) characteristic of CLL are found in MBL. Although limited, genetic studies using next-generation sequencing (NGS) reveal similarities between MBL and early-stage CLL (Rasi et al 2012;Greco et al 2013;Ojha et al 2014;Agathangelidis et al 2018;Popp et al 2019). MBL and CLL samples have similar mutation burdens; however, when analyzed for specific driver mutations, less are found in MBL (Puente et al 2015), consistent with the stepwise evolution from one to the other.…”

Section: Monoclonal B-cell Lymphocytosismentioning

confidence: 99%

Chronic Lymphocytic Leukemia

Chiorazzi

Chen

Kanti

2020

Cold Spring Harb Perspect Med

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Accumulation of DNA damage and alteration of the DNA damage response in monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia

Cited by 10 publications

References 52 publications

Involvement of classic and alternative non-homologous end joining pathways in hematologic malignancies: targeting strategies for treatment

Involvement of classic and alternative non-homologous end joining pathways in hematologic malignancies: targeting strategies for treatment

Increased frequencies of IgH locus suicide recombination points on Chronic Lymphocytic Leukemia with low rate of AID related somatic mutations, cMYC overexpression and short telomeres

Chronic Lymphocytic Leukemia

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