NF-κB-dependent DNA damage-signaling differentially regulates DNA double-strand break repair mechanisms in immature and mature human hematopoietic cells

Kraft, Daniela; Rall, Melanie; Volcic, Meta; Metzler, Eric; Groo, Anne-Claire; Stahl, Andreea; Bauer, Louisa; Nasonova, Elena; Salles, Daniela C.; Taucher-Scholz, G.; Bönig, Halvard; Fournier, Claudia; Wiesmüller, Lisa

doi:10.1038/leu.2015.28

Cited by 40 publications

(63 citation statements)

References 60 publications

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“…Moreover, signaling between hematopoietic stem and hematopoietic stem progenitor cells (HSPC) are different phenomena as was shown recently: nuclear factor kappa-lightchain-enhancer of activated B cells (NF-κB) signaling is the molecular component underlying the observed differences between HSPC and PBL [68]. NF-κB activation has been reviewed [17,18] and shown to be activated by stromal cell-related cytokines of inflammation such as tumor necrosis factor alpha (TNF-α) [69].…”

Section: Genes Are Not Blueprintsmentioning

confidence: 99%

Somatic Mutation Theory - Why it's Wrong for Most Cancers

Brücher¹,

Jamall

2016

Cell Physiol Biochem

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Hysteron proteron reverses both temporal and logical order and this syllogism occurs in carcinogenesis and the somatic mutation theory (SMT): the first (somatic mutation) occurs only after the second (onset of cancer) and, therefore, observed somatic mutations in most cancers appear well after the early cues of carcinogenesis are in place. It is no accident that mutations are increasingly being questioned as the causal event in the origin of the vast majority of cancers as clinical data show little support for this theory when compared against the metrics of patient outcomes. Ever since the discovery of the double helical structure of DNA, virtually all chronic diseases came to be viewed as causally linked to one degree or another to mutations, even though we now know that genes are not simply blueprints, but rather an assemblage of alphabets that can, under non-genetic influences, be used to assemble a business letter or a work of Shakespearean literature. A minority of all cancers is indeed caused by mutations but the SMT has been applied to all cancers, and even to chemical carcinogenesis, in the absence of hard evidence of causality. Herein, we review the 100 year story of SMT and aspects that show why genes are not just blueprints, how radiation and mutation are associated in a more nuanced view, the proposed risk of cancer and bad luck, and the in vitro and in vivo evidence for a new cancer paradigm. This paradigm is scientifically applicable for the majority of non-heritable cancers and consists of a six-step sequence for the origin of cancer. This new cancer paradigm proclaims that somatic mutations are epiphenomena or later events occurring after carcinogenesis is already underway. This serves not just as a plausible alternative to SMT and explains the origin of the majority of cancers, but also provides opportunities for early interventions and prevention of the onset of cancer as a disease.

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Section: Genes Are Not Blueprintsmentioning

confidence: 99%

Somatic Mutation Theory - Why it's Wrong for Most Cancers

Brücher¹,

Jamall

2016

Cell Physiol Biochem

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“…In addition, we also found INPP4B knockdown can inhibit the nuclear translocation of p65, activation of p65 nuclear translocation by TNF-α can reverse the INPP4B knockdown-induced upregulation of p-H2AX expression and downregulation of ATM, p-ATM, p-ATR, p-BRCA1, and p-RAD51. Concomitantly, TNF-α can also reverse INPP4B knockdown-induced sensitizing effect, with a higher cell viabilities compared with INPP4B siRNA alone in condition of cytarabine treatment, suggesting the NF-KB subunit, p65, nuclear translocation At present, the attention to the relation between NF-KB signaling and DNA repair is increasing, It is reported that NF-kBdependent DNA damage-signaling regulates DNA doublestrand break repair mechanisms in mature peripheral blood lymphocytes [32], and NF-KB subunit, p50, can regulate FANCD2 expression in multiple myeloma [33]. Other literatures also showed that DNA damage can activate NF-KB pathway via ATM activation [34], however, in our study, we found ATM expression was regulated by NF-KB activation.…”

Section: Discussionmentioning

confidence: 95%

INPP4B-mediated DNA repair pathway confers resistance to chemotherapy in acute myeloid leukemia

Wang

et al. 2016

Tumor Biol.

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INPP4B has been recently shown to be a poor prognostic marker and confer chemo- or radio-resistance in AML cells, whereas, the underlying mechanisms remain unclear. Herein, we aimed to explore the possible mechanisms mediated the resistance to chemotherapy in AML. We found that INPP4B-mediated resistance to genotoxic drug, cytarabine, was accompanied by lower p-H2AX accumulation in KG-1 cells, and INPP4B knockdown evidently sensitized KG-1 cells to cytarabine, meanwhile, p-H2AX expression was increased dramatically. Then, we observed that INPP4B knockdown inhibited the loss of p-H2AX expression after cytarabine removal in INPP4B-silenced KG-1 cells, whereas, in control KG-1 cells, the expression of p-H2AX was reduced in a time-dependent manner. Next, INPP4B knockdown can significantly downregulate ATM expression and subsequently inhibit the activation of ATM downstream targets of p-ATM, p-BRCA1, p-ATR, and p-RAD51. Furthermore, nuclear localization of p65 was inhibited after INPP4B knockdown, and reactivation of p65 can rescue the INPP4B knockdown-induced inhibition of ATM, p-ATM, p-BRCA1, p-ATR, and p-RAD51. Finally, INPP4B expression was positively correlated with ATM expression in AML cells, both INPP4B knockdown and KU55933 can significantly sensitize primary myeloid leukemic cells to cytarabine treatment.Collectively, these data suggest that enhanced ATM-dependent DNA repair is involved in resistance to chemotherapy in INPP4B AML, which could be mediated by p65 nuclear translocation, combination chemotherapy with INPP4B or DNA repair pathway inhibition represents a promising strategy in INPP4B AML.

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“…This might be explained by other pro-death signals of the heavy ion exposure. Interestingly, in human hematopoietic stem and progenitor cells (HSPC) and peripheral blood lymphocytes (PBL), inhibition of NF-κB activation by expression of a super-repressor variant of IκBα (IκBα-SR) altered DNA double-strand-break repair [52]. IκBα-SR expression reduced homologous DSB repair in PBL by 33% [52].…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, in human hematopoietic stem and progenitor cells (HSPC) and peripheral blood lymphocytes (PBL), inhibition of NF-κB activation by expression of a super-repressor variant of IκBα (IκBα-SR) altered DNA double-strand-break repair [52]. IκBα-SR expression reduced homologous DSB repair in PBL by 33% [52]. NHEJ of DNA DSBs was compromised in HSPC and PBL (reduction to 37% and 52%, respectively) [52].…”

Section: Discussionmentioning

confidence: 99%

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The Role of the Nuclear Factor κB Pathway in the Cellular Response to Low and High Linear Energy Transfer Radiation

Hellweg

Spitta

Koch

et al. 2018

IJMS

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Astronauts are exposed to considerable doses of space radiation during long-term space missions. As complete shielding of the highly energetic particles is impracticable, the cellular response to space-relevant radiation qualities has to be understood in order to develop countermeasures and to reduce radiation risk uncertainties. The transcription factor Nuclear Factor κB (NF-κB) plays a fundamental role in the immune response and in the pathogenesis of many diseases. We have previously shown that heavy ions with a linear energy transfer (LET) of 100–300 keV/µm have a nine times higher potential to activate NF-κB compared to low-LET X-rays. Here, chemical inhibitor studies using human embryonic kidney cells (HEK) showed that the DNA damage sensor Ataxia telangiectasia mutated (ATM) and the proteasome were essential for NF-κB activation in response to X-rays and heavy ions. NF-κB’s role in cellular radiation response was determined by stable knock-down of the NF-κB subunit RelA. Transfection of a RelA short-hairpin RNA plasmid resulted in higher sensitivity towards X-rays, but not towards heavy ions. Reverse Transcriptase real-time quantitative PCR (RT-qPCR) showed that after exposure to X-rays and heavy ions, NF-κB predominantly upregulates genes involved in intercellular communication processes. This process is strictly NF-κB dependent as the response is completely absent in RelA knock-down cells. NF-κB’s role in the cellular radiation response depends on the radiation quality.

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NF-κB-dependent DNA damage-signaling differentially regulates DNA double-strand break repair mechanisms in immature and mature human hematopoietic cells

Cited by 40 publications

References 60 publications

Somatic Mutation Theory - Why it's Wrong for Most Cancers

Somatic Mutation Theory - Why it's Wrong for Most Cancers

INPP4B-mediated DNA repair pathway confers resistance to chemotherapy in acute myeloid leukemia

The Role of the Nuclear Factor κB Pathway in the Cellular Response to Low and High Linear Energy Transfer Radiation

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