Publications by authors named "Toshiya Inaba"

74 Publications

Revertant somatic mosaicism as a cause of cancer.

Cancer Sci 2021 Apr 2;112(4):1383-1389. Epub 2021 Mar 2.

Department of Molecular Oncology and Leukemia Program Project, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.

Revertant (somatic) mosaicism is a spontaneous correction of a causative mutation in patients with congenital diseases. A relatively frequent event, revertant mosaicism may bring favorable outcomes that ameliorate disorders, and is therefore called "natural gene therapy." However, it has been revealed recently that "overcorrection" of inherited bone marrow failure in patients with sterile alpha motif domain containing 9 (SAMD9)/9L syndromes by revertant mosaicism induces myelodysplastic syndrome (MDS) with monosomy 7 that occasionally proceeds to acute myelogenous leukemia (AML). In this review, we interpret very complex mechanisms underlying MDS/AML in patients with SAMD9/9L syndromes. This includes multiple myeloid tumor suppressors on the long arm of chromosome 7, all of which act in a haploinsufficient fashion, and a difference in sensitivity to interferon between cells carrying a mutation and revertants. Overcorrection of mutants by somatic mosaicism is likely a novel mechanism in carcinogenesis.
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http://dx.doi.org/10.1111/cas.14852DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8019205PMC
April 2021

Multiorgan failure with abnormal receptor metabolism in mice mimicking Samd9/9L syndromes.

J Clin Invest 2021 Feb;131(4)

Department of Molecular Oncology and Leukemia Program Project, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.

Autosomal dominant sterile α motif domain containing 9 (Samd9) and Samd9L (Samd9/9L) syndromes are a large subgroup of currently established inherited bone marrow failure syndromes that includes myelodysplasia, infection, growth restriction, adrenal hypoplasia, genital phenotypes, and enteropathy (MIRAGE), ataxia pancytopenia, and familial monosomy 7 syndromes. Samd9/9L genes are located in tandem on chromosome 7 and have been known to be the genes responsible for myeloid malignancies associated with monosomy 7. Additionally, as IFN-inducible genes, Samd9/9L are crucial for protection against viruses. Samd9/9L syndromes are caused by gain-of-function mutations and develop into infantile myelodysplastic syndromes associated with monosomy 7 (MDS/-7) at extraordinarily high frequencies. We generated mice expressing Samd9LD764N, which mimic MIRAGE syndrome, presenting with growth retardation, a short life, bone marrow failure, and multiorgan degeneration. In hematopoietic cells, Samd9LD764N downregulates the endocytosis of transferrin and c-Kit, resulting in a rare cause of anemia and a low bone marrow reconstitutive potential that ultimately causes MDS/-7. In contrast, in nonhematopoietic cells we tested, Samd9LD764N upregulated the endocytosis of EGFR by Ship2 phosphatase translocation to the cytomembrane and activated lysosomes, resulting in the reduced expression of surface receptors and signaling. Thus, Samd9/9L is a downstream regulator of IFN that controls receptor metabolism, with constitutive activation leading to multiorgan dysfunction.
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http://dx.doi.org/10.1172/JCI140147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880413PMC
February 2021

UTX maintains the functional integrity of the murine hematopoietic system by globally regulating aging-associated genes.

Blood 2021 Feb;137(7):908-922

Human Disease Models, Institute of Laboratory Animals, Tokyo Women's Medical University, Tokyo, Japan.

Epigenetic regulation is essential for the maintenance of the hematopoietic system, and its deregulation is implicated in hematopoietic disorders. In this study, UTX, a demethylase for lysine 27 on histone H3 (H3K27) and a component of COMPASS-like and SWI/SNF complexes, played an essential role in the hematopoietic system by globally regulating aging-associated genes. Utx-deficient (UtxΔ/Δ) mice exhibited myeloid skewing with dysplasia, extramedullary hematopoiesis, impaired hematopoietic reconstituting ability, and increased susceptibility to leukemia, which are the hallmarks of hematopoietic aging. RNA-sequencing (RNA-seq) analysis revealed that Utx deficiency converted the gene expression profiles of young hematopoietic stem-progenitor cells (HSPCs) to those of aged HSPCs. Utx expression in hematopoietic stem cells declined with age, and UtxΔ/Δ HSPCs exhibited increased expression of an aging-associated marker, accumulation of reactive oxygen species, and impaired repair of DNA double-strand breaks. Pathway and chromatin immunoprecipitation analyses coupled with RNA-seq data indicated that UTX contributed to hematopoietic homeostasis mainly by maintaining the expression of genes downregulated with aging via demethylase-dependent and -independent epigenetic programming. Of note, comparison of pathway changes in UtxΔ/Δ HSPCs, aged muscle stem cells, aged fibroblasts, and aged induced neurons showed substantial overlap, strongly suggesting common aging mechanisms among different tissue stem cells.
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http://dx.doi.org/10.1182/blood.2019001044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918186PMC
February 2021

Activation of CpG-Rich Promoters Mediated by MLL Drives MOZ-Rearranged Leukemia.

Cell Rep 2020 09;32(13):108200

Tsuruoka Metabolomics Laboratory, National Cancer Center, Tsuruoka, Yamagata 997-0052, Japan; Division of Hematological Malignancy, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan. Electronic address:

Uncontrolled self-renewal of hematopoietic progenitors induces leukemia. To self-renew, leukemia cells must continuously activate genes that were previously active in their mother cells. Here, we describe the circuitry of a transactivation system responsible for oncogenic self-renewal. MLL recruits RNA polymerase II (RNAP2) to unmethylated CpG-rich promoters by its CXXC domain and activates transcription by transcriptional regulators, including the AF4 family/ENL family/P-TEFb complex, DOT1L, and p300/CBP histone acetyl transferases. MOZ also targets a broad range of CpG-rich promoters through association with RNAP2 and MLL. Leukemic fusion proteins such as MOZ-TIF2 and MLL-AFX constitutively activate CpG-rich promoters by aberrantly recruiting p300/CBP. Pharmacological inhibition of MLL or DOT1L induces differentiation of MOZ-TIF2-transformed cells. These results reveal that activation of unmethylated CpG-rich promoters mediated by MLL is the central mechanism of oncogenic self-renewal in MOZ-rearranged leukemia and indicate that the molecularly targeted therapies intended for MLL-rearranged leukemia can be applied for MOZ-rearranged leukemia.
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http://dx.doi.org/10.1016/j.celrep.2020.108200DOI Listing
September 2020

Association between low doses of ionizing radiation, administered acutely or chronically, and time to onset of stroke in a rat model.

J Radiat Res 2020 Sep;61(5):666-673

International University of Health and Welfare Clinic, Otawara, Tochigi, Japan.

Exposure to high-doses of ionizing radiation has been reported to be associated with the risk of stroke. However, risks associated with lower dose exposures remain unclear, and there is little information available for the risk modification according to the dose-rate. There are few studies using animal models which might be able to provide complementary information on this association. In this study, the male stroke-prone spontaneously hypertensive rat (SHRSP) was used as a model animal. The rats were acutely irradiated with doses between 0 and 1.0 Gy or chronically irradiated with a cumulative dose of 0.5 or 1.0 Gy (at a dose rate of 0.05 or 0.1 Gy/day, respectively). The onset time of stroke related symptoms in SHRSP was used as an endpoint for evaluating the effects of low dose and the low dose-rate gamma-ray exposures. With respect to acute exposure, the time to the onset of stroke in the irradiated rats suggested the presence of a threshold around 0.1 Gy. For the low dose-rate chronically exposed, no significant increase in stroke symptom was observed. These findings are novel and demonstrate that the SHRSP system can be used to determine the association between the risk of stroke and radiation exposure with high sensitivity. Moreover, these studies provide important information regarding the association between the low dose and low dose-rate radiation exposure and circulatory diseases, especially stroke.
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http://dx.doi.org/10.1093/jrr/rraa050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7482173PMC
September 2020

Association of aberrant ASNS imprinting with asparaginase sensitivity and chromosomal abnormality in childhood BCP-ALL.

Blood 2020 11;136(20):2319-2333

Department of Pediatrics and.

Karyotype is an important prognostic factor in childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL), but the underlying pharmacogenomics remain unknown. Asparaginase is an integral component in current chemotherapy for childhood BCP-ALL. Asparaginase therapy depletes serum asparagine. Normal hematopoietic cells can produce asparagine by asparagine synthetase (ASNS) activity, but ALL cells are unable to synthesize adequate amounts of asparagine. The ASNS gene has a typical CpG island in its promoter. Thus, methylation of the ASNS CpG island could be one of the epigenetic mechanisms for ASNS gene silencing in BCP-ALL. To gain deep insights into the pharmacogenomics of asparaginase therapy, we investigated the association of ASNS methylation status with asparaginase sensitivity. The ASNS CpG island is largely unmethylated in normal hematopoietic cells, but it is allele-specifically methylated in BCP-ALL cells. The ASNS gene is located at 7q21, an evolutionally conserved imprinted gene cluster. ASNS methylation in childhood BCP-ALL is associated with an aberrant methylation of the imprinted gene cluster at 7q21. Aberrant methylation of mouse Asns and a syntenic imprinted gene cluster is also confirmed in leukemic spleen samples from ETV6-RUNX1 knockin mice. In 3 childhood BCP-ALL cohorts, ASNS is highly methylated in BCP-ALL patients with favorable karyotypes but is mostly unmethylated in BCP-ALL patients with poor prognostic karyotypes. Higher ASNS methylation is associated with higher L-asparaginase sensitivity in BCP-ALL through lower ASNS gene and protein expression levels. These observations demonstrate that silencing of the ASNS gene as a result of aberrant imprinting is a pharmacogenetic mechanism for the leukemia-specific activity of asparaginase therapy in BCP-ALL.
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http://dx.doi.org/10.1182/blood.2019004090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7702480PMC
November 2020

HHEX promotes myeloid transformation in cooperation with mutant ASXL1.

Blood 2020 10;136(14):1670-1684

Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.

Additional sex combs-like 1 (ASXL1), an epigenetic modulator, is frequently mutated in myeloid neoplasms. Recent analyses of mutant ASXL1 conditional knockin (ASXL1-MT-KI) mice suggested that ASXL1-MT alone is insufficient for myeloid transformation. In our previous study, we used retrovirus-mediated insertional mutagenesis, which exhibited the susceptibility of ASXL1-MT-KI hematopoietic cells to transform into myeloid leukemia cells. In this screening, we identified the hematopoietically expressed homeobox (HHEX) gene as one of the common retrovirus integration sites. In this study, we investigated the potential cooperation between ASXL1-MT and HHEX in myeloid leukemogenesis. Expression of HHEX enhanced proliferation of ASXL1-MT-expressing HSPCs by inhibiting apoptosis and blocking differentiation, whereas it showed only modest effect in normal HSPCs. Moreover, ASXL1-MT and HHEX accelerated the development of RUNX1-ETO9a and FLT3-ITD leukemia. Conversely, HHEX depletion profoundly attenuated the colony-forming activity and leukemogenicity of ASXL1-MT-expressing leukemia cells. Mechanistically, we identified MYB and ETV5 as downstream targets for ASXL1-MT and HHEX by using transcriptome and chromatin immunoprecipitation-next-generation sequencing analyses. Moreover, we found that expression of ASXL1-MT enhanced the binding of HHEX to the promoter loci of MYB or ETV5 via reducing H2AK119ub. Depletion of MYB or ETV5 induced apoptosis or differentiation in ASXL1-MT-expressing leukemia cells, respectively. In addition, ectopic expression of MYB or ETV5 reversed the reduced colony-forming activity of HHEX-depleted ASXL1-MT-expressing leukemia cells. These findings indicate that the HHEX-MYB/ETV5 axis promotes myeloid transformation in ASXL1-mutated preleukemia cells.
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http://dx.doi.org/10.1182/blood.2019004613DOI Listing
October 2020

Effects of Radiation on Blood Pressure and Body Weight in the Spontaneously Hypertensive Rat Model. Are Radiation Effects on Blood Pressure Affected by Genetic Background?

Radiat Res 2020 06;193(6):552-559

International University of Health and Welfare Clinic, Tochigi, 324-8501, Japan.

In this work, we utilized spontaneously hypertensive rats (SHR) and Wister Kyoto rats (WKY), from which the SHR was established, to evaluate the effects of whole-body acute radiation on the cardiovascular system at doses from 0 to 4 Gy. In the irradiated SHR, the systolic blood pressure (SBP) increased with increasing dose, while body weight gain decreased with increasing radiation dose. Furthermore, pathological observations of SHR demonstrated that the number of rats with cystic degeneration in the liver increased with increasing dose. The effects observed among SHR, such as increased SBP and retardation of body weight gain, appear very similar to those observed in Japanese atomic bomb survivors. In contrast, the SBP among WKY did not change relative to dose; the body weight, however, did change, as in the SHR. Therefore, the association between radiation exposure and SBP, but not between radiation exposure and retardation of body weight gain, may be affected by genetic background, as evident from strain difference. These results suggest that the SHR and WKY animal models may be useful for studying radiation effects on non-cancer diseases including circulatory diseases, chronic liver disease and developmental retardation.
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http://dx.doi.org/10.1667/RR15536.1DOI Listing
June 2020

Molecular pathogenesis of progression to myeloid leukemia from TET-insufficient status.

Blood Adv 2020 03;4(5):845-854

Department of Hematology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.

Loss-of-function mutations in ten-eleven translocation-2 (TET2) are recurrent events in acute myeloid leukemia (AML) as well as in preleukemic hematopoietic stem cells (HSCs) of age-related clonal hematopoiesis. TET3 mutations are infrequent in AML, but the level of TET3 expression in HSCs has been found to decline with age. We examined the impact of gradual decrease of TET function in AML development by generating mice with Tet deficiency at various degrees. Tet2f/f and Tet3f/f mice were crossed with mice expressing Mx1-Cre to generate Tet2f/wtTet3f/fMx-Cre+ (T2ΔT3), Tet2f/fTet3f/wtMx-Cre+ (ΔT2T3), and Tet2f/fTet3f/fMx-Cre+ (ΔT2ΔT3) mice. All ΔT2ΔT3 mice died of aggressive AML at a median survival of 10.7 weeks. By comparison, T2ΔT3 and ΔT2T3 mice developed AML at longer latencies, with a median survival of ∼27 weeks. Remarkably, all 9 T2ΔT3 and 8 ΔT2T3 mice with AML showed inactivation of the remaining nontargeted Tet2 or Tet3 allele, respectively, owing to exonic loss in either gene or stop-gain mutations in Tet3. Recurrent mutations other than Tet3 were not noted in any mice by whole-exome sequencing. Spontaneous inactivation of residual Tet2 or Tet3 alleles is a recurrent genetic event during the development of AML with Tet insufficiency.
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http://dx.doi.org/10.1182/bloodadvances.2019001324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7065477PMC
March 2020

Deficiency Activates Inflammatory Pathways, Promotes M2 Macrophage Polarization, and Causes Bladder Cancer in Cooperation with Dysfunction.

Clin Cancer Res 2020 04 11;26(8):2065-2079. Epub 2020 Feb 11.

Field of Human Disease Models, Major in Advanced Life Sciences and Medicine, Institute of Laboratory Animals, Tokyo Women's Medical University, Shinjuku-ku, Tokyo, Japan.

Purpose: Epigenetic deregulation is deeply implicated in the pathogenesis of bladder cancer. KDM6A (Lysine (K)-specific demethylase 6A) is a histone modifier frequently mutated in bladder cancer. However, the molecular mechanisms of how KDM6A deficiency contributes to bladder cancer development remains largely unknown. We hypothesized that clarification of the pathogenic mechanisms underlying -mutated bladder cancer can help in designing new anticancer therapies.

Experimental Design: We generated mice lacking in the urothelium and crossed them with mice heterozygous for , whose mutation/deletion significantly overlaps with the mutation in muscle-invasive bladder cancer (MIBC). In addition, BBN (N-butyl-N-(4-hydroxybutyl) nitrosamine), a cigarette smoke-like mutagen, was used as a tumor-promoting agent. Isolated urothelia were subjected to phenotypic, pathologic, molecular, and cellular analyses. The clinical relevance of our findings was further analyzed using genomic and clinical data of patients with MIBC.

Results: We found that deficiency activated cytokine and chemokine pathways, promoted M2 macrophage polarization, increased cancer stem cells and caused bladder cancer in cooperation with haploinsufficiency. We also found that BBN treatment significantly enhanced the expression of proinflammatory molecules and accelerated disease development. Human bladder cancer samples with decreased expression also showed activated proinflammatory pathways. Notably, dual inhibition of IL6 and chemokine (C-C motif) ligand 2, upregulated in response to deficiency, efficiently suppressed -deficient bladder cancer cell growth.

Conclusions: Our findings provide insights into multistep carcinogenic processes of bladder cancer and suggest molecular targeted therapeutic approaches for patients with bladder cancer with dysfunction.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-2230DOI Listing
April 2020

BRD4-Regulated Molecular Targets in Mantle Cell Lymphoma: Insights into Targeted Therapeutic Approach.

Cancer Genomics Proteomics 2020 Jan-Feb;17(1):77-89

Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan

Background: Since bromodomain-containing protein 4 (BRD4) facilitates the transcription of genes important for neoplastic cells in a cancer-type specific manner, BRD4-regulated molecules may also include therapeutic targets for mantle cell lymphoma (MCL), a treatment-refractory subtype of malignant lymphoma.

Materials And Methods: In order to uncover direct BRD4-regulated targets in MCL, we performed integrated analysis using the pathway database and the results of both gene-expression profiling and chromatin immunoprecipitation with parallel sequencing for BRD4.

Results: Treatment with BRD4 inhibitor I-BET151 exerted a dose-dependent inhibitory effect on cell proliferation in MCL cell lines. BRD4 was found to directly regulate series of genes involved in the B-cell receptor (BCR) signaling pathway, including B-cell linker (BLNK), paired box 5 (PAX5), and IKAROS family zinc finger 3 (IKZF3), and several oncogenes, such as MYB. Indeed, the combinatory inhibition of BCR pathway and IKZF showed an additive antitumor effect.

Conclusion: Concomitant targeting multiple BRD4-regulated molecules may constitute a rational therapeutic strategy for MCL.
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http://dx.doi.org/10.21873/cgp.20169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6937128PMC
June 2020

Kinetics of cytokine receptor internalization under steady-state conditions affects growth of neighboring blood cells.

Haematologica 2020 07 31;105(7):e325-e327. Epub 2019 Oct 31.

Department of Molecular Oncology and Leukemia Program Project, Research Institute for Radiation Biology & Medicine, Hiroshima University, Minami-ku, Hiroshima.

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http://dx.doi.org/10.3324/haematol.2019.232959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7327623PMC
July 2020

[Monosomy 7: recent progress].

Rinsho Ketsueki 2019 ;60(9):1020-1026

Department of Molecular Oncology and Leukemia Program Project, Research Institute for Radiation Biology and Medicine, Hiroshima University.

Fifty years after its discovery, the enigma of monosomy 7 (-7) is eventually unraveling. The key to understanding -7 is "haploinsufficiency" mechanism, through which the function of myeloid tumor-suppressor genes is lost via the deletion/mutation of one allele. In this century, powerful tools such as microarray-CGH and next generation sequencing have enabled the search for tumor-suppressor genes on chromosome 7. Five genes (Samd9, Samd9-like (Samd9L), Ezh2, MLL3, and CUX1) have been identified and their myeloid tumor suppression potential has been verified using mouse models. Mice lacking one Samd9L gene developed MDS at an advanced age, whereas mice children harboring a gain-of-function mutation of Samd9 or Samd9L gene suffer from bone marrow failure, which is frequently followed by childhood MDS with -7, suggesting that these tumor-suppressor genes are the key to understanding not only MDS with -7 but also MDS in general. However, lack of Ezh2 and MLL3, which encode epigenetic regulators, contribute to the promotion of the progression of myeloid tumor cells that harbor abnormalities in the p53 or Ras pathways.
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http://dx.doi.org/10.11406/rinketsu.60.1020DOI Listing
October 2019

Resistance of t(17;19)-acute lymphoblastic leukemia cell lines to multiagents in induction therapy.

Cancer Med 2019 Sep 15;8(11):5274-5288. Epub 2019 Jul 15.

Department of Pediatrics, School of Medicine, University of Yamanashi, Chuo, Japan.

t(17;19)(q21-q22;p13), responsible for TCF3-HLF fusion, is a rare translocation in childhood B-cell precursor acute lymphoblastic leukemia(BCP-ALL). t(1;19)(q23;p13), producing TCF3-PBX1 fusion, is a common translocation in childhood BCP-ALL. Prognosis of t(17;19)-ALL is extremely poor, while that of t(1;19)-ALL has recently improved dramatically in intensified chemotherapy. In this study, TCF3-HLF mRNA was detectable at a high level during induction therapy in a newly diagnosed t(17;19)-ALL case, while TCF3-PBX1 mRNA was undetectable at the end of induction therapy in most newly diagnosed t(1;19)-ALL cases. Using 4 t(17;19)-ALL and 16 t(1;19)-ALL cell lines, drug response profiling was analyzed. t(17;19)-ALL cell lines were found to be significantly more resistant to vincristine (VCR), daunorubicin (DNR), and prednisolone (Pred) than t(1;19)-ALL cell lines. Sensitivities to three (Pred, VCR, and l-asparaginase [l-Asp]), four (Pred, VCR, l-Asp, and DNR) and five (Pred, VCR, l-Asp, DNR, and cyclophosphamide) agents, widely used in induction therapy, were significantly poorer for t(17;19)-ALL cell lines than for t(1;19)-ALL cell lines. Consistent with poor responses to VCR and DNR, gene and protein expression levels of P-glycoprotein (P-gp) were higher in t(17;19)-ALL cell lines than in t(1;19)-ALL cell lines. Inhibitors for P-gp sensitized P-gp-positive t(17;19)-ALL cell lines to VCR and DNR. Knockout of P-gp by CRISPRCas9 overcame resistance to VCR and DNR in the P-gp-positive t(17;19)-ALL cell line. A combination of cyclosporine A with DNR prolonged survival of NSG mice inoculated with P-gp-positive t(17;19)-ALL cell line. These findings indicate involvement of P-gp in resistance to VCR and DNR in Pgp positive t(17;19)-ALL cell lines. In all four t(17;19)-ALL cell lines, RAS pathway mutation was detected. Furthermore, among 16 t(1;19)-ALL cell lines, multiagent resistance was usually observed in the cell lines with RAS pathway mutation in comparison to those without it, suggesting at least a partial involvement of RAS pathway mutation in multiagent resistance of t(17;19)-ALL.
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http://dx.doi.org/10.1002/cam4.2356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6718581PMC
September 2019

The enigma of monosomy 7.

Blood 2018 06 3;131(26):2891-2898. Epub 2018 Apr 3.

Department of Molecular Laboratory Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.

Since a report of some 50 years ago describing refractory anemia associated with group C monosomy, monosomy 7 (-7) and interstitial deletions of chromosome 7 (del(7q)) have been established as one of the most frequent chromosomal aberrations found in essentially all types of myeloid tumors regardless of patient age and disease etiology. In the last century, researchers sought recessive myeloid tumor-suppressor genes by attempting to determine commonly deleted regions (CDRs) in del(7q) patients. However, these efforts were not successful. Today, tumor suppressors located in 7q are believed to act in a haploinsufficient fashion, and powerful new technologies such as microarray comparative genomic hybridization and high-throughput sequencing allow comprehensive searches throughout the genes encoded on 7q. Among those proposed as promising candidates, 4 have been validated by gene targeting in mouse models. (sterile α motif domain 9) and (SAMD9-like) encode related endosomal proteins, mutations of which cause hereditary diseases with strong propensity to infantile myelodysplastic syndrome (MDS) harboring monosomy 7. Because MDS develops in -deficient mice over their lifetime, / are likely responsible for sporadic MDS with -7/del(7q) as the sole anomaly. (enhancer of zeste homolog 2) and (mixed lineage leukemia 3) encode histone-modifying enzymes; loss-of-function mutations of these are detected in some myeloid tumors at high frequencies. In contrast to /, loss of or likely contributes to myeloid tumorigenesis in cooperation with additional specific gene alterations such as of or genes involved in the p53/Ras pathway, respectively. Distinctive roles with different significance of the loss of multiple responsible genes render the complex nature of myeloid tumors carrying -7/del(7q).
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http://dx.doi.org/10.1182/blood-2017-12-822262DOI Listing
June 2018

A novel ASXL1-OGT axis plays roles in H3K4 methylation and tumor suppression in myeloid malignancies.

Leukemia 2018 06 3;32(6):1327-1337. Epub 2018 Mar 3.

Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, 1088639, Japan.

ASXL1 plays key roles in epigenetic regulation of gene expression through methylation of histone H3K27, and disruption of ASXL1 drives myeloid malignancies, at least in part, via derepression of posterior HOXA loci. However, little is known about the identity of proteins that interact with ASXL1 and about the functions of ASXL1 in modulation of the active histone mark, such as H3K4 methylation. In this study, we demonstrate that ASXL1 is a part of a protein complex containing HCFC1 and OGT; OGT directly stabilizes ASXL1 by O-GlcNAcylation. Disruption of this novel axis inhibited myeloid differentiation and H3K4 methylation as well as H2B glycosylation and impaired transcription of genes involved in myeloid differentiation, splicing, and ribosomal functions; this has implications for myelodysplastic syndrome (MDS) pathogenesis, as each of these processes are perturbed in the disease. This axis is responsible for tumor suppression in the myeloid compartment, as reactivation of OGT induced myeloid differentiation and reduced leukemogenecity both in vivo and in vitro. Our data also suggest that MLL5, a known HCFC1/OGT-interacting protein, is responsible for gene activation by the ASXL1-OGT axis. These data shed light on the novel roles of the ASXL1-OGT axis in H3K4 methylation and activation of transcription.
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http://dx.doi.org/10.1038/s41375-018-0083-3DOI Listing
June 2018

Dose-response curves for analyzing of dicentric chromosomes and chromosome translocations following doses of 1000 mGy or less, based on irradiated peripheral blood samples from five healthy individuals.

J Radiat Res 2018 Jan;59(1):35-42

Department of Radiation Life Sciences, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima, 960-1295, Japan.

In terms of biological dosimetry at the time of radiation exposure, the dicentric chromosome (Dic) assay (DCA) is the gold standard for assessing for the acute phase and chromosome translocation (Tr) analysis is the gold standard for assessing the chronic phase. It is desirable to have individual dose-response curves (DRCs) for each laboratory because the analysis criteria differ between laboratories. We constructed the DRCs for radiation dose estimation (with three methods) using peripheral blood (PB) samples from five healthy individuals. Aliquots were irradiated with one of eight gamma-ray doses (0, 10, 20, 50, 100, 200, 500 or 1000 mGy), then cultured for 48 h. The number of chromosome aberrations (CAs) was analyzed by DCA, using Giemsa staining and centromere-fluorescence in situ hybridization (centromere-FISH) and by chromosome painting (chromosome pairs 1, 2 and 4) for Tr analysis. In DCA, there was large variation between individuals in the frequency of Dics formed, and the slopes of the DRCs were different. In Tr analysis, although variation was observed in the frequency of Tr, the slopes of the DRCs were similar after adjusting the background for age. Good correlation between the irradiation dose and the frequency of CAs formed was observed with these three DRCs. However, performing three different biological dosimetry assays simultaneously on PB from five donors nonetheless results in variation in the frequency of CAs formed, especially at doses of 50 mGy or less, highlighting the difficulty of biological dosimetry using these methods. We conclude that it might be difficult to construct universal DRCs.
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http://dx.doi.org/10.1093/jrr/rrx052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5786284PMC
January 2018

Priming of lineage-specifying genes by Bcl11b is required for lineage choice in post-selection thymocytes.

Nat Commun 2017 09 26;8(1):702. Epub 2017 Sep 26.

Laboratory for Transcriptional Regulation, RIKEN Center for Integrative Medical Sciences (IMS), 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, 230-0045, Japan.

T-lineage committed precursor thymocytes are screened by a fate-determination process mediated via T cell receptor (TCR) signals for differentiation into distinct lineages. However, it remains unclear whether any antecedent event is required to couple TCR signals with the transcriptional program governing lineage decisions. Here we show that Bcl11b, known as a T-lineage commitment factor, is essential for proper expression of ThPOK and Runx3, central regulators for the CD4-helper/CD8-cytotoxic lineage choice. Loss of Bcl11b results in random expression of these factors and, thereby, lineage scrambling that is disconnected from TCR restriction by MHC. Initial Thpok repression by Bcl11b prior to the pre-selection stage is independent of a known silencer for Thpok, and requires the last zinc-finger motif in Bcl11b protein, which by contrast is dispensable for T-lineage commitment. Collectively, our findings shed new light on the function of Bcl11b in priming lineage-specifying genes to integrate TCR signals into subsequent transcriptional regulatory mechanisms.CD4 and CD8 T cells develop in the thymus with their transcription programs controlled by ThPOK and Runx3, respectively. Here the authors show that a pre-commitment event modulated by the transcription factor, Bcl11b, is required for the proper expression of ThPOK and Runx3 and correct CD4/CD8 lineage commitment.
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http://dx.doi.org/10.1038/s41467-017-00768-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5615048PMC
September 2017

A Chemical Modulator of p53 Transactivation that Acts as a Radioprotective Agonist.

Mol Cancer Ther 2018 02 22;17(2):432-442. Epub 2017 Sep 22.

Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.

Inhibiting p53-dependent apoptosis by inhibitors of p53 is an effective strategy for preventing radiation-induced damage in hematopoietic lineages, while p53 and p21 also play radioprotective roles in the gastrointestinal epithelium. We previously identified some zinc(II) chelators, including 8-quinolinol derivatives, that suppress apoptosis in attempts to discover compounds that target the zinc-binding site in p53. We found that 5-chloro-8-quinolinol (5CHQ) has a unique p53-modulating activity that shifts its transactivation from proapoptotic to protective responses, including enhancing p21 induction and suppressing PUMA induction. This p53-modulating activity also influenced p53 and p53-target gene expression in unirradiated cells without inducing DNA damage. The specificity of 5CHQ for p53 and p21 was demonstrated by silencing the expression of each protein. These effects seem to be attributable to the sequence-specific alteration of p53 DNA-binding, as evaluated by chromatin immunoprecipitation and electrophoretic mobility shift assays. In addition, 5-chloro-8-methoxyquinoline itself had no antiapoptotic activity, indicating that the hydroxyl group at the 8-position is required for its antiapoptotic activity. We applied this remarkable agonistic activity to protecting the hematopoietic and gastrointestinal system in mouse irradiation models. The dose reduction factors of 5CHQ in total-body and abdominally irradiated mice were about 1.2 and 1.3, respectively. 5CHQ effectively protected mouse epithelial stem cells from a lethal dose of abdominal irradiation. Furthermore, the specificity of 5CHQ for p53 in reducing the lethality induced by abdominal irradiation was revealed in -KO mice. These results indicate that the pharmacologic upregulation of radioprotective p53 target genes is an effective strategy for addressing the gastrointestinal syndrome.
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http://dx.doi.org/10.1158/1535-7163.MCT-16-0554DOI Listing
February 2018

Acquired expression of in mice induces dysplastic myelopoiesis mimicking chronic myelomonocytic leukemia.

Blood 2017 04 16;129(15):2148-2160. Epub 2017 Feb 16.

Department of Disease Model, Research Institute of Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.

Chronic myelomonocytic leukemia (CMML) is a hematological malignancy characterized by uncontrolled proliferation of dysplastic myelomonocytes and frequent progression to acute myeloid leukemia (AML). We identified mutations in the gene, which encodes a negative regulator of cytokine signaling, in a subset of CMML patients. To investigate the contribution of mutant in CMML pathogenesis, we generated conditional knockin mice for that express wild-type in a steady state and inducibly express , a CMML-associated mutant. mice exhibited sustained proliferation of myelomonocytes, multilineage dysplasia, and splenomegaly, which are the hallmarks of CMML. The phosphatidylinositol 3-kinase (PI3K)-AKT and JAK-STAT pathways were constitutively activated in hematopoietic stem cells, which promoted cell cycle progression and enhanced chemokine-chemokine receptor activity. , a gene encoding a GTPase that is upregulated by , enhanced hematopoietic stem cell activity and induced myeloid cell proliferation. In addition, , a gene encoding a transcription factor, was found to cooperate with and progress CMML to AML. Furthermore, targeted inhibition for the PI3K-AKT and JAK-STAT pathways efficiently suppressed the proliferative activity of -bearing CMML cells. Our findings provide insights into the molecular mechanisms underlying mutant -induced CMML and propose a possible molecular targeting therapy for mutant -carrying CMML patients.
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http://dx.doi.org/10.1182/blood-2016-06-724658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5391621PMC
April 2017

Propagation of trimethylated H3K27 regulated by polycomb protein EED is required for embryogenesis, hematopoietic maintenance, and tumor suppression.

Proc Natl Acad Sci U S A 2016 09 30;113(37):10370-5. Epub 2016 Aug 30.

Department of Disease Model, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima 734-8553, Japan;

Polycomb repressive complex 2 (PRC2) catalyzes the monomethylation, dimethylation, and trimethylation of histone H3 Lys27 (H3K27) and acts as a central epigenetic regulator that marks the repressive chromatin domain. Embryonic ectoderm development (EED), an essential component of PRC2, interacts with trimethylated H3K27 (H3K27me3) through the aromatic cage structure composed of its three aromatic amino acids, Phe97, Trp364, and Tyr365. This interaction allosterically activates the histone methyltransferase activity of PRC2 and thereby propagates repressive histone marks. In this study, we report the analysis of knock-in mice harboring the myeloid disorder-associated EED Ile363Met (I363M) mutation, analogous to the EED aromatic cage mutants. The I363M homozygotes displayed a remarkable and preferential reduction of H3K27me3 and died at midgestation. The heterozygotes increased the clonogenic capacity and bone marrow repopulating activity of hematopoietic stem/progenitor cells (HSPCs) and were susceptible to leukemia. Lgals3, a PRC2 target gene encoding a multifunctional galactose-binding lectin, was derepressed in I363M heterozygotes, which enhanced the stemness of HSPCs. Thus, our work provides in vivo evidence that the structural integrity of EED to H3K27me3 propagation is critical, especially for embryonic development and hematopoietic homeostasis, and that its perturbation increases the predisposition to hematologic malignancies.
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http://dx.doi.org/10.1073/pnas.1600070113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5027452PMC
September 2016

Maintenance of the functional integrity of mouse hematopoiesis by EED and promotion of leukemogenesis by EED haploinsufficiency.

Sci Rep 2016 07 19;6:29454. Epub 2016 Jul 19.

Department of Disease Model, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan.

Polycomb repressive complex 2 (PRC2) participates in transcriptional repression through methylation of histone H3K27. The WD-repeat protein embryonic ectoderm development (EED) is a non-catalytic but an essential component of PRC2 and its mutations were identified in hematopoietic malignancies. To clarify the role(s) of EED in adult hematopoiesis and leukemogenesis, we generated Eed conditional knockout (Eed(Δ/Δ)) mice. Eed(Δ/Δ) mice died in a short period with rapid decrease of hematopoietic cells. Hematopoietic stem/progenitor cells (HSPCs) were markedly decreased with impaired bone marrow (BM) repopulation ability. Cell cycle analysis of HSPCs demonstrated increased S-phase fraction coupled with suppressed G0/G1 entry. Genes encoding cell adhesion molecules are significantly enriched in Eed(Δ/Δ) HSPCs, and consistently, Eed(Δ/Δ) HSPCs exhibited increased attachment to a major extracellular matrix component, fibronectin. Thus, EED deficiency increases proliferation on one side but promotes quiescence possibly by enhanced adhesion to the hematopoietic niche on the other, and these conflicting events would lead to abnormal differentiation and functional defect of Eed(Δ/Δ) HSPCs. In addition, Eed haploinsufficiency induced hematopoietic dysplasia, and Eed heterozygous mice were susceptible to malignant transformation and developed leukemia in cooperation with Evi1 overexpression. Our results demonstrated differentiation stage-specific and dose-dependent roles of EED in normal hematopoiesis and leukemogenesis.
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http://dx.doi.org/10.1038/srep29454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4949429PMC
July 2016

Biological implications of somatic DDX41 p.R525H mutation in acute myeloid leukemia.

Exp Hematol 2016 08 9;44(8):745-754.e4. Epub 2016 May 9.

Department of Molecular Oncology and Leukemia Program Project, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan; Department of Molecular Laboratory Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; Central Clinical Laboratory, Kumamoto University Hospital, Kumamoto, Japan. Electronic address:

The DDX41 gene, encoding a DEAD-box type ATP-dependent RNA helicase, is rarely but reproducibly mutated in myeloid diseases. The acquired mutation in DDX41 is highly concentrated at c.G1574A (p.R525H) in the conserved motif VI located at the C-terminus of the helicase core domain where ATP interacts and is hydrolyzed. Therefore, it is likely that the p.R525H mutation perturbs ATPase activity in a dominant-negative manner. In this study, we screened for the DDX41 mutation of CD34-positive tumor cells based on mRNA sequencing and identified the p.R525H mutation in three cases among 23 patients. Intriguingly, these patients commonly exhibited acute myeloid leukemia (AML) with peripheral blood cytopenias and low blast counts, suggesting that the mutation inhibits the growth and differentiation of hematopoietic cells. Data from cord blood cells and leukemia cell lines suggest a role for DDX41 in preribosomal RNA processing, in which the expression of the p.R525H mutant causes a certain ribosomopathy phenotype in hematopoietic cells by suppressing MDM2-mediated RB degradation, thus triggering the inhibition of E2F activity. This study uncovered a pathogenic role of p.R525H DDX41 in the slow growth rate of tumor cells. Age-dependent epigenetic alterations or other somatic changes might collaborate with the mutation to cause AML.
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http://dx.doi.org/10.1016/j.exphem.2016.04.017DOI Listing
August 2016

Identification of cooperative genes for E2A-PBX1 to develop acute lymphoblastic leukemia.

Cancer Sci 2016 Jul 13;107(7):890-8. Epub 2016 Jun 13.

Department of Disease Model, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.

E2A-PBX1 is a chimeric gene product detected in t(1;19)-bearing acute lymphoblastic leukemia (ALL) with B-cell lineage. To investigate the leukemogenic process, we generated conditional knock-in (cKI) mice for E2A-PBX1, in which E2A-PBX1 is inducibly expressed under the control of the endogenous E2A promoter. Despite the induced expression of E2A-PBX1, no hematopoietic disease was observed, strongly suggesting that additional genetic alterations are required to develop leukemia. To address this possibility, retroviral insertional mutagenesis was used. Virus infection efficiently induced T-cell, B-cell, and biphenotypic ALL in E2A-PBX1 cKI mice. Inverse PCR identified eight retroviral common integration sites, in which enhanced expression was observed in the Gfi1, Mycn, and Pim1 genes. In addition, it is of note that viral integration and overexpression of the Zfp521 gene was detected in one tumor with B-cell lineage; we previously identified Zfp521 as a cooperative gene with E2A-HLF, another E2A-involving fusion gene with B-lineage ALL. The cooperative oncogenicity of E2A-PBX1 with overexpressed Zfp521 in B-cell tumorigenesis was indicated by the finding that E2A-PBX1 cKI, Zfp521 transgenic compound mice developed B-lineage ALL. Moreover, upregulation of ZNF521, the human counterpart of Zfp521, was found in several human leukemic cell lines bearing t(1;19). These results indicate that E2A-PBX1 cooperates with additional gene alterations to develop ALL. Among them, enhanced expression of ZNF521 may play a clinically relevant role in E2A fusion genes to develop B-lineage ALL.
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http://dx.doi.org/10.1111/cas.12945DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4946715PMC
July 2016

Involvement of resistin-like molecule β in the development of methionine-choline deficient diet-induced non-alcoholic steatohepatitis in mice.

Sci Rep 2016 Jan 28;6:20157. Epub 2016 Jan 28.

Department of Medical Science, Graduate School of Medicine, University of Hiroshima, 1-2-3 Kasumi, Minami-ku, Hiroshima City, Hiroshima Japan.

Resistin-like molecule β (RELMβ) reportedly has multiple functions including local immune responses in the gut. In this study, we investigated the possible contribution of RELMβ to non-alcoholic steatohepatitis (NASH) development. First, RELMβ knock-out (KO) mice were shown to be resistant to methionine-choline deficient (MCD) diet-induced NASH development. Since it was newly revealed that Kupffer cells in the liver express RELMβ and that RELMβ expression levels in the colon and the numbers of RELMβ-positive Kupffer cells were both increased in this model, we carried out further experiments using radiation chimeras between wild-type and RELMβ-KO mice to distinguish between the contributions of RELMβ in these two organs. These experiments revealed the requirement of RELMβ in both organs for full manifestation of NASH, while deletion of each one alone attenuated the development of NASH with reduced serum lipopolysaccharide (LPS) levels. The higher proportion of lactic acid bacteria in the gut microbiota of RELMβ-KO than in that of wild-type mice may be one of the mechanisms underlying the lower serum LPS level the former. These data suggest the contribution of increases in RELMβ in the gut and Kupffer cells to NASH development, raising the possibility of RELMβ being a novel therapeutic target for NASH.
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http://dx.doi.org/10.1038/srep20157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4730188PMC
January 2016

Fbxl10 overexpression in murine hematopoietic stem cells induces leukemia involving metabolic activation and upregulation of Nsg2.

Blood 2015 May 14;125(22):3437-46. Epub 2015 Apr 14.

Department of Disease Model and.

We previously reported that deficiency for Samd9L, which was cloned as a candidate gene for -7/7q- syndrome, accelerated leukemia cooperatively with enhanced expression of a histone demethylase: F-box and leucine-rich repeat protein 10 (Fbxl10, also known as Jhdm1b, Kdm2b, and Ndy1). To further investigate the role of Fbxl10 in leukemogenesis, we generated transgenic (Tg) mice that overexpress Fbxl10 in hematopoietic stem cells (HSCs). Interestingly, Fbxl10 Tg mice developed myeloid or B-lymphoid leukemia with complete penetrance. HSCs from the Tg mice exhibited an accelerated G0/G1-to-S transition with a normal G0 to G1 entry, resulting in pleiotropic progenitor cell expansion. Fbxl10 Tg HSCs displayed enhanced expression of neuron-specific gene family member 2 (Nsg2), and forced expression of Nsg2 in primary bone marrow cells resulted in expansion of immature cells. In addition, the genes involved in mitochondrial oxidative phosphorylation were markedly enriched in Fbxl10 Tg HSCs, coupled with increased cellular adenosine 5'-triphosphate levels. Moreover, chromatin immunoprecipitation followed by sequencing analysis demonstrated that Fbxl10 directly binds to the regulatory regions of Nsg2 and oxidative phosphorylation genes. These findings define Fbxl10 as a bona fide oncogene, whose deregulated expression contributes to the development of leukemia involving metabolic proliferative advantage and Nsg2-mediated impaired differentiation.
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http://dx.doi.org/10.1182/blood-2014-03-562694DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4447860PMC
May 2015

A novel ATM/TP53/p21-mediated checkpoint only activated by chronic γ-irradiation.

PLoS One 2014 5;9(8):e104279. Epub 2014 Aug 5.

Department of Molecular Radiobiology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.

Different levels or types of DNA damage activate distinct signaling pathways that elicit various cellular responses, including cell-cycle arrest, DNA repair, senescence, and apoptosis. Whereas a range of DNA-damage responses have been characterized, mechanisms underlying subsequent cell-fate decision remain elusive. Here we exposed cultured cells and mice to different doses and dose rates of γ-irradiation, which revealed cell-type-specific sensitivities to chronic, but not acute, γ-irradiation. Among tested cell types, human fibroblasts were associated with the highest levels of growth inhibition in response to chronic γ-irradiation. In this context, fibroblasts exhibited a reversible G1 cell-cycle arrest or an irreversible senescence-like growth arrest, depending on the irradiation dose rate or the rate of DNA damage. Remarkably, when the same dose of γ-irradiation was delivered chronically or acutely, chronic delivery induced considerably more cellular senescence. A similar effect was observed with primary cells isolated from irradiated mice. We demonstrate a critical role for the ataxia telangiectasia mutated (ATM)/tumor protein p53 (TP53)/p21 pathway in regulating DNA-damage-associated cell fate. Indeed, blocking the ATM/TP53/p21 pathway deregulated DNA damage responses, leading to micronucleus formation in chronically irradiated cells. Together these results provide insights into the mechanisms governing cell-fate determination in response to different rates of DNA damage.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0104279PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4122452PMC
November 2015

AS-2, a novel inhibitor of p53-dependent apoptosis, prevents apoptotic mitochondrial dysfunction in a transcription-independent manner and protects mice from a lethal dose of ionizing radiation.

Biochem Biophys Res Commun 2014 Aug 12;450(4):1498-504. Epub 2014 Jul 12.

Center for Technologies against Cancer, Tokyo University of Science, Chiba 278-8510, Japan; Department of Medicinal and Life Science, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba 278-8510, Japan.

In a previous study, we reported that some tetradentate zinc(II) chelators inhibit p53 through the denaturation of its zinc-requiring structure but a chelator, Bispicen, a potent inhibitor of in vitro apoptosis, failed to show any efficient radioprotective effect against irradiated mice because the toxicity of the chelator to mice. The unsuitability of using tetradentate chelators as radioprotectors prompted us to undertake a more extensive search for p53-inhibiting agents that are weaker zinc(II) chelators and therefore less toxic. Here, we show that an 8-hydroxyquinoline (8HQ) derivative, AS-2, suppresses p53-dependent apoptosis through a transcription-independent mechanism. A mechanistic study using cells with different p53 characteristics revealed that the suppressive effect of AS-2 on apoptosis is specifically mediated through p53. In addition, AS-2 was less effective in preventing p53-mediated transcription-dependent events than pifithrin-μ (PFTμ), an inhibitor of transcription-independent apoptosis by p53. Fluorescence visualization of the extranuclear distribution of AS-2 also supports that it is ineffective on the transcription-dependent pathway. Further investigations revealed that AS-2 suppressed mitochondrial apoptotic events, such as the mitochondrial release of intermembrane proteins and the loss of mitochondrial membrane potential, although AS-2 resulted in an increase in the mitochondrial translocation of p53 as opposed to the decrease of cytosolic p53, and did not affect the apoptotic interaction of p53 with Bcl-2. AS-2 also protected mice that had been exposed to a lethal dose of ionizing radiation. Our findings indicate that some types of bidentate 8HQ chelators could serve as radioprotectors with no substantial toxicity in vivo.
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http://dx.doi.org/10.1016/j.bbrc.2014.07.037DOI Listing
August 2014