Increase of DNA damage and alteration of the DNA damage response in myelodysplastic syndromes and acute myeloid leukemias

Popp, Henning D.; Naumann, Nicole; Brendel, Susanne; Henzler, Thomas; Weiß, Christel; Hofmann, Wolf‐Karsten; Fabarius, Alice

doi:10.1016/j.leukres.2017.03.011

Cited by 33 publications

(36 citation statements)

References 39 publications

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“…Activation of DNA damage checkpoints characterizes BM from patients with MDS, as detected by immunostaining of ATM, Chk2, and gH2AX. 53,54 Inactivation of DNA damage checkpoints correlates with RAEB2 21 and AML, 43 as well as disease progression from MDS to acute leukemia. 53 Consistent with impaired DNA damage checkpoints in monosomy 7 cells, we observed decreased apoptosis signaling in these cells, and further genomic instability consequent to failure of these regulatory pathways was suggested by markedly increased mutations in monosomy 7 cells in 1 of our patients.…”

Section: Discussionmentioning

confidence: 99%

Single-cell RNA-seq reveals a distinct transcriptome signature of aneuploid hematopoietic cells

Zhao

Gao

et al. 2017

Blood

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Section: Discussionmentioning

confidence: 99%

Single-cell RNA-seq reveals a distinct transcriptome signature of aneuploid hematopoietic cells

Zhao

Gao

et al. 2017

Blood

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“…γH2AX and 53BP1 were detected in the PBMCs of healthy donors and CML patients using a mouse monoclonal anti-γH2AX antibody (clone JBW301; Merck Millipore, Darmstadt, Germany) and a polyclonal rabbit anti-53BP1 antibody (NB100-304; Novus Biologicals, Littleton, US), respectively. An Alexa Fluor 488-conjugated goat anti-mouse antibody and an Alexa Fluor 555-conjugated goat anti-rabbit antibody (Thermo Fisher Scientific) were used as previously described [38,39]. At least 50 PBMCs were analyzed for each measurement.…”

Section: Immunofluorescence Staining Of γH2ax and 53bp1mentioning

confidence: 99%

“…Western blotting of (p-)ATM and (p-)CHK2 was conducted in the PBMCs of healthy donors, CP-CML patients in DMR or MMR, CP-CML patients with loss of MMR, de novo untreated CP-CML patients, and BP-CML patients as previously described [39]. (p-)ATM and (p-)CHK2 expressing SKM-1 acute myeloid leukemia cells (Leibniz Institute DSMZ-German Collection of Microorganisms and Cell Cultures GmbH, Braunschweig, Germany) served as positive control.…”

Section: Western Blottingmentioning

confidence: 99%

DNA Damage and DNA Damage Response in Chronic Myeloid Leukemia

Popp

Kohl

Naumann

et al. 2020

IJMS

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DNA damage and alterations in the DNA damage response (DDR) are critical sources of genetic instability that might be involved in BCR-ABL1 kinase-mediated blastic transformation of chronic myeloid leukemia (CML). Here, increased DNA damage is detected by γH2AX foci analysis in peripheral blood mononuclear cells (PBMCs) of de novo untreated chronic phase (CP)-CML patients (n = 5; 2.5 γH2AX foci per PBMC ± 0.5) and blast phase (BP)-CML patients (n = 3; 4.4 γH2AX foci per PBMC ± 0.7) as well as CP-CML patients with loss of major molecular response (MMR) (n = 5; 1.8 γH2AX foci per PBMC ± 0.4) when compared to DNA damage in PBMC of healthy donors (n = 8; 1.0 γH2AX foci per PBMC ± 0.1) and CP-CML patients in deep molecular response or MMR (n = 26; 1.0 γH2AX foci per PBMC ± 0.1). Progressive activation of erroneous non-homologous end joining (NHEJ) repair mechanisms during blastic transformation in CML is indicated by abundant co-localization of γH2AX/53BP1 foci, while a decline of the DDR is suggested by defective expression of (p-)ATM and (p-)CHK2. In summary, our data provide evidence for the accumulation of DNA damage in the course of CML and suggest ongoing DNA damage, erroneous NHEJ repair mechanisms, and alterations in the DDR as critical mediators of blastic transformation in CML.

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“…Interestingly, the inhibition of ATR but not ATM improves erythroid differentiation, suggesting that mitigating the DNA damage signaling might be useful for the prevention/treatment of MDS. The activation of the DDR characterizes many bone-marrow specimens from MDS patients, according to immunostaining analysis with antibodies anti p-ATM, p-Chk2, and gH2AX, showing highest expression levels especially in patients with late refractory anemia with excess blasts (RAEB-1) [25,26]. This activation of the DDR appears associated with unscheduled DNA replication and activation of ATM, and is not seen in during the progression to overt leukemia, coincident with loss of one or both ATM alleles [26].…”

Section: The Essential Function Of Ddr In the Maintenance Of Hscsmentioning

confidence: 99%