In mammalian cells, the DNA damage response (DDR) prevents the replication and propagation of DNA errors to the next generation, thus maintaining genomic stability. At the heart of the DDR are the ...related signaling kinases ATM, ATR, and DNA-PK, which regulate DNA repair and associated events such as cell cycle checkpoints, chromatin remodeling, transcription, and ultimately apoptosis. Several findings highlight the occurrence of DDR in hemopoietic stem cells (HSCs), and persistence of DNA lesions in these cells promotes their functional decline and accumulation of leukemogenic mutations. Besides favoring tumor formation and progression, molecular defects that directly or indirectly inactivate certain DDR pathways can provide a therapeutic opportunity, since a reduced ability to repair DNA lesions renders hemopoietic malignancies vulnerable to genotoxic drugs acting also through synthetic lethal interactions. Here, we discuss the essential role of DDR in HSC maintenance and protection against leukemogenesis, and how acquired DDR dysfunctions or pharmacological agents that block this pathway can be effectively exploited for the treatment of various hematopoietic malignancies.
The XCIND syndrome is named after distinct hypersensitivity to ionizing (
X
-ray) irradiation, cancer susceptibility,
i
mmunodeficiency,
n
eurological abnormality, and double-strand DNA breakage. The ...disorders comprising XCIND syndrome are usually inherited in an autosomal recessive manner. Ataxia telangiectasia (A-T) is one such disease, and is caused by biallelic germline mutation of the Ataxia telangiectasia mutated (
ATM
) gene. Heterozygous carriers of the
ATM
mutation, who do not show A-T-like clinical symptoms, are estimated to comprise 1 % of the population. Thus, understanding the biological basis of XCIND, including A-T, should help shed light on the pathogenesis of genetic diseases with cancer susceptibility.
The Ewing sarcoma breakpoint region 1 (EWSR1) gene is known to fuse with various partner genes to promote the development of the Ewing sarcoma family of tumors and other sarcomas. In contrast, the ...association of EWSR1 chimeric fusion genes with leukemia has rarely been reported. We identified a novel EWSR1‐associated chimeric fusion gene in a patient with acute myeloid leukemia harboring 46, XY, t (11; 22) (p13; q12) karyotype abnormality. The patient was refractory to intensified chemotherapy including hematopoietic stem cell transplantation. Total RNA paired‐end sequencing identified a novel chimeric fusion gene as EWSR1/ELF5, a member of the E26 transformation‐specific transcription factor family. Transduction of EWSR1/ELF5 to NIH3T3 cells induced transformation by attenuating with the p53/p21‐dependent pathway. The injection of EWSR1/ELF5‐transduced NIH3T3 cells into NSG‐SCID mice systematically induced the development of tumors in vivo. These results revealed the oncogenic potency of EWSR1/ELF5.
Novel chimeric fusion gene, EWSR1/ELF5, was identified in a patient with acute myeloid leukemia (AML). EWSR1/ELF5 induced cetllular transformation by attenuating with the p53/p21‐dependent pathway.
Background Low birth weight (LBW) and fetal growth restriction are associated with the development of cardio-metabolic diseases later in life. A recent Mendelian randomization study concluded that ...the susceptibility of LBW infants to develop hypertension during adulthood is due to the inheritance of hypertension genes from the mother and not to an unfavorable intrauterine environment. Therein, a negative linear association has been assumed between genetically estimated maternal blood pressure (BP) and birth weight, while the observed relationship between maternal BP and birth weight is substantially different from that assumption. As many hypertension genes are likely involved in vasculature development and function, we hypothesized that BP-increasing genetic variants could affect birth weight by reducing the growth of the placenta, a highly vascular organ, without overtly elevating the maternal BP. Methods Using a birth cohort in the Japanese population possessing time-series fetal growth velocity data as a target and a GWAS summary statistics of BioBank Japan as a base data, we performed polygenic score (PGS) analyses for systolic BP (SBP), diastolic BP, mean arterial pressure, and pulse pressure. A causal mediation analysis was performed to assess the meditation effect of placental weight on birth weight reduced by maternal BP-increasing PGS. Maternal genetic risk score constituted of only "vasculature-related" BP single nucleotide polymorphisms (SNPs) was constructed to examine the involvement of vascular genes in the mediation effect of placental weight. We identified gestational week in which maternal SBP-increasing PGS significantly decreased fetal growth velocity. Results We observed that maternal SBP-increasing PGS was negatively associated with offspring birth weight. A causal mediation analysis revealed that a large proportion of the total maternal PGS effect on birth weight was mediated by placental weight. The placental mediation effect was remarkable when genetic risk score was constituted of "vasculature-related" BP SNPs. The inverse association between maternal SBP PGS and fetal growth velocity only became apparent in late gestation. Conclusions Our study suggests that maternal hypertension genes are strongly associated with placental growth and that fetal growth inhibition is induced through the intrauterine environment established by the placenta. Keywords: Intrauterine programming, Placenta, Blood pressure, Vascular genes, Developmental Origin of Health and Disease (DOHaD)
Neither accurate incidence nor survival data for pediatric patients with hematological malignancies (HM) have been available in Japan to date. Incidence of patients under 20 years of age, who were ...diagnosed with HM from 2006 to 2010, and their two-year survival rate (2y-OS) were obtained from disease registry data maintained by the Japan Society of Pediatric Hematology (JSPH). A total of 5,287 cases of HM were identified during this period. Acute lymphoblastic leukemia (ALL, 46.6 %) showed the highest incidence, followed by acute myeloid leukemia (AML, 16.7 %), non-Hodgkin lymphoma (NHL, 11.9 %), and histiocytosis (11.8 %). ALL, AML and histiocytosis were common in younger patients aged 1–4, while NHL tended to occur more frequently in older patients aged 5–14. The 2y-OS of HM was 91.6 %, with that for the most common B-precursor ALL rising to 96.2 %. The 2y-OS for M3 AML, lymphoblastic-B-precursor or diffuse large B cell NHL, Hodgkin lymphoma, myeloproliferative disorders, and Langerhans cell histiocytosis was >95 %. There were no gender differences in prognosis, while infants (88.0 %) and adolescents aged 15–19 (90.6 %) tended toward a poorer prognosis. This is the first report to describe incidence and survival times from the nationwide JSPH disease registry. More precise data with longer follow-up is needed.
The function of the kinase Btk in neutrophil activation is largely unexplored. Here we found that Btk-deficient neutrophils had more production of reactive oxygen species (ROS) after engagement of ...Toll-like receptors (TLRs) or receptors for tumor-necrosis factor (TNF), which was associated with more apoptosis and was reversed by transduction of recombinant Btk. Btk-deficient neutrophils in the resting state showed hyperphosphorylation and activation of phosphatidylinositol-3-OH kinase (PI(3)K) and protein tyrosine kinases (PTKs) and were in a 'primed' state with plasma membrane-associated GTPase Rac2. In the absence of Btk, the adaptor Mal was associated with PI(3)K and PTKs at the plasma membrane, whereas in control resting neutrophils, Btk interacted with and confined Mal in the cytoplasm. Our data identify Btk as a critical gatekeeper of neutrophil responses.
Abstract Poly (ADP-ribose) polymerase (PARP) is an indispensable component of the DNA repair machinery. PARP inhibitors are used as cutting-edge treatments for patients with homologous recombination ...repair (HRR)-defective breast cancers harboring mutations in BRCA1 or BRCA2 . Other tumors defective in HRR, including some hematological malignancies, are predicted to be good candidates for treatment with PARP inhibitors. Screening of leukemia-derived cell lines revealed that lymphoid lineage–derived leukemia cell lines, except for those derived from mature B cells and KMT2A ( MLL )-rearranged B-cell precursors, were relatively sensitive to PARP inhibitors. By contrast, acute myelogenous leukemia cell lines, except for RUNX1-RUNXT1 (AML1-ETO)-positive lines, were relatively resistant. Intriguingly, TCF3 (E2A)-HLF–positive leukemia was sensitive to PARP inhibitors. TCF3-HLF expression suppressed HRR activity, suggesting that PARP inhibitor treatment induced synthetic lethality. Furthermore, TCF3-HLF expression decreased levels of MCPH1, which regulates the expression of BRCA1, resulting in attenuation of HRR activity. The PARP inhibitor olaparib was also effective in an in vivo xenograft model. Our results suggest a novel therapeutic approach for treating refractory leukemia, particularly the TCF3-HLF–positive subtype.
► Type 1 diabetes upregulated a set of genes including Serpine1 in endothelium. ► Serpine1 upregulation by diabetes persisted after normoglycemic cell culture. ► High glucose-treatment only partially ...mimicked the effect of type 1 diabetes. ► Serpine1 promoter in diabetic endothelium was enriched with H3K4me3 modification.
Clinical trials with type 1 and type 2 diabetes have identified a phenomenon known as “metabolic memory” in which previous periods of hyperglycemia result in the long-lasting deleterious impact on cardiovascular events. Emerging evidence shows that transient hyperglycemic exposure of human endothelial cells induces histone 3 lysine 4 mono-methylation (H3K4me1) on the promoter and persistent mRNA expression of RelA and IL-8 genes, suggesting that epigenetic histone modification and chromatin structure remodeling is a key event underlying metabolic memory. This burgeoning hypothesis, however, critically remains to be tested for relevance in the disease process of diabetes in vivo, and for broader applicability to an array of genes involved in endothelial dysfunction. To address this, we used type 1 diabetes mouse model induced by streptozocin to be hyperglycemic for 8weeks, and isolated endothelial cells that were used either freshly after isolation or after 2 to 3-week cell culture in normoglycemic conditions. mRNA expression profiling in diabetic mouse endothelial cells revealed significant and persistent up-regulation of Serpine1 encoding PAI-1, the hypo-fibrinolytic mediator leading to thrombotic diseases in diabetes, along with Rock2, Fn1 and Ccl2, whereas only Serpine 1 was persistently elevated in high glucose-treated mouse endothelial cells. Chromosome immunoprecipitation assay in type 1 diabetic mouse endothelial cells showed predominant enrichment of H3K4 tri-methylation on Serpine1 promoter, suggesting a unique epigenetic regulation in diabetic mice as opposed to high glucose-treated human ECs. Our study demonstrates the importance of combining in vivo models of diabetes with high glucose-treated cell culture to better assess the epigenetic mechanisms relevant to disease.
Tyrosine kinase 2 (Tyk2) is a nonreceptor tyrosine kinase that belongs to the Janus kinase (Jak) family. Here we identified a homozygous Tyk2 mutation in a patient who had been clinically diagnosed ...with hyper-IgE syndrome. This patient showed unusual susceptibility to various microorganisms including virus, fungi, and mycobacteria and suffered from atopic dermatitis with elevated serum IgE. The patient's cells displayed defects in multiple cytokine signaling pathways including those for type I interferon (IFN), interleukin (IL)-6, IL-10, IL-12, and IL-23. The cytokine signals were successfully restored by transducing the intact Tyk2 gene. Thus, the Tyk2 deficiency is likely to account for the patient's complex clinical manifestations, including the phenotype of impaired T helper 1 (Th1) differentiation and accelerated Th2 differentiation. This study identifies human Tyk2 deficiency and demonstrates that Tyk2 plays obligatory roles in multiple cytokine signals involved in innate and acquired immunity of humans, which differs substantially from Tyk2 function in mice.
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