Addiction to RUNX in lymphoma

No abstract available

RUNX oncoproteins and miRNA networks

News on: An AML1-ETO/miR-29b-1 regulatory circuit modulates phenotypic properties of acute myeloid leukemia cells by Zaidi et al. Oncotarget. 2017; 8:39994-40005. https://doi.org/10.18632/oncotarget.18127

RUNX-mediated growth arrest and senescence are attenuated by diverse mechanisms in cells expressing RUNX1 fusion oncoproteins

RUNX gene over-expression inhibits growth of primary cells but transforms cells with tumor suppressor defects, consistent with reported associations with tumor progression. In contrast, chromosomal translocations involving RUNX1 are detectable in utero, suggesting an initiating role in leukemias. How do cells expressing RUNX1 fusion oncoproteins evade RUNX-mediated growth suppression? Previous studies showed that the TEL-RUNX1 fusion from t(12;21) B-ALLs is unable to induce senescence-like growth arrest (SLGA) in primary fibroblasts while potent activity is displayed by the RUNX1-ETO fusion found in t(8;21) AMLs. We now show that SLGA potential is suppressed in TEL-RUNX1 but reactivated by deletion of the TEL HLH domain or mutation of a key residue (K99R). Attenuation of SLGA activity is also a feature of RUNX1-ETO9a, a minor product of t(8;21) translocations with increased leukemogenicity. Finally, while RUNX1-ETO induces SLGA it also drives a potent senescence-associated secretory phenotype (SASP), and promotes the immortalisation of rare cells that escape SLGA. Moreover, the RUNX1-ETO SASP is not strictly linked to growth arrest as it is largely suppressed by RUNX1 and partially activated by RUNX1-ETO9a. These findings underline the heterogeneous nature of premature senescence and the multiple mechanisms by which this failsafe process is subverted in cells expressing RUNX1 oncoproteins

The protein kinase C inhibitor, Ro-31-7459, is a potent activator of ERK and JNK MAP kinases in HUVECs and yet inhibits cyclic AMP-stimulated <i>SOCS-3</i> gene induction through inactivation of the transcription factor c-Jun

Induction of the suppressor of cytokine signalling 3 (SOCS-3) gene is vital to the normal control of inflammatory signalling. In order to understand these processes we investigated the role of the proto-oncogene component of the AP-1 transcription factor complex, c-Jun, in the regulation of SOCS-3 gene induction. We found that cyclic AMP stimulation of HUVECs promoted phosphorylation and activation of JNK MAP kinase and its substrate c-Jun. The JNK responsive element of the human SOCS-3 promoter mapped to a putative AP-1 site within 1000 bp of the transcription start site. The PKC inhibitors, GF-109203X, Gö-6983 and Ro-317549, were all found to inhibit AP-1 transcriptional activity, transcriptional activation of this minimal SOCS-3 promoter and SOCS-3 gene induction in HUVECs. Interestingly, Ro-317549 treatment was also found to promote PKC-dependent activation of ERK and JNK MAP kinases and promote JNK-dependent hyper-phosphorylation of c-Jun, whereas GF-109203X and Gö-6983 had little effect. Despite this, all three PKC inhibitors were found to be effective inhibitors of c-Jun DNA-binding activity. The JNK-dependent hyper-phosphorylation of c-Jun in response to Ro-317549 treatment of HUVECs does therefore not interfere with its ability to inhibit c-Jun activity and acts as an effective inhibitor of c-Jun-dependent SOCS-3 gene induction

RNA polymerase III, ageing and longevity

Transcription in eukaryotic cells is performed by three RNA polymerases. RNA polymerase I synthesises most rRNAs, whilst RNA polymerase II transcribes all mRNAs and many non-coding RNAs. The largest of the three polymerases is RNA polymerase III (Pol III) which transcribes a variety of short non-coding RNAs including tRNAs and the 5S rRNA, in addition to other small RNAs such as snRNAs, snoRNAs, SINEs, 7SL RNA, Y RNA, and U6 spilceosomal RNA. Pol III-mediated transcription is highly dynamic and regulated in response to changes in cell growth, cell proliferation and stress. Pol III-generated transcripts are involved in a wide variety of cellular processes, including translation, genome and transcriptome regulation and RNA processing, with Pol III dys-regulation implicated in diseases including leukodystrophy, Alzheimer’s, Fragile X-syndrome and various cancers. More recently, Pol III was identified as an evolutionarily conserved determinant of organismal lifespan acting downstream of mTORC1. Pol III inhibition extends lifespan in yeast, worms and flies, and in worms and flies acts from the intestine and intestinal stem cells respectively to achieve this. Intriguingly, Pol III activation achieved through impairment of its master repressor, Maf1, has also been shown to promote longevity in model organisms, including mice. In this review we introduce the Pol III transcription apparatus and review the current understanding of RNA Pol III’s role in ageing and lifespan in different model organisms. We then discuss the potential of Pol III as a therapeutic target to improve age-related health in humans

Addiction to Runx1 is partially attenuated by loss of p53 in the Eμ-Myc lymphoma model

The Runx genes function as dominant oncogenes that collaborate potently with Myc or loss of p53 to induce lymphoma when over-expressed. Here we examined the requirement for basal Runx1 activity for tumor maintenance in the Eµ-Myc model of Burkitt’s lymphoma. While normal Runx1fl/fl lymphoid cells permit mono-allelic deletion, primary Eµ-Myc lymphomas showed selection for retention of both alleles and attempts to enforce deletion in vivo led to compensatory expansion of p53null blasts retaining Runx1. Surprisingly, Runx1 could be excised completely from established Eµ- Myc lymphoma cell lines in vitro without obvious effects on cell phenotype. Established lines lacked functional p53, and were sensitive to death induced by introduction of a temperature-sensitive p53 (Val135) allele. Transcriptome analysis of Runx1-deleted cells revealed a gene signature associated with lymphoid proliferation, survival and differentiation, and included strong de-repression of recombination-activating (Rag) genes, an observation that was mirrored in a panel of human acute leukemias where RUNX1 and RAG1,2 mRNA expression were negatively correlated. Notably, despite their continued growth and tumorigenic potential, Runx1null lymphoma cells displayed impaired proliferation and markedly increased sensitivity to DNA damage and dexamethasone-induced apoptosis, validating Runx1 function as a potential therapeutic target in Myc-driven lymphomas regardless of their p53 status

Polr3b heterozygosity in mice induces both beneficial and deleterious effects on health during ageing with no effect on lifespan

The genetic pathways that modulate ageing in multicellular organisms are typically highly conserved across wide evolutionary distances. Recently RNA polymerase III (Pol III) was shown to promote ageing in yeast, C. elegans and D. melanogaster. In this study we investigated the role of Pol III in mammalian ageing using C57BL/6N mice heterozygous for Pol III (Polr3b+/−). We identified sexually dimorphic, organ-specific beneficial as well as detrimental effects of the Polr3b+/− mutation on health. Female Polr3b+/− mice displayed improved bone health during ageing, but their ability to maintain an effective gut barrier function was compromised and they were susceptible to idiopathic dermatitis (ID). In contrast, male Polr3b+/− mice were lighter than wild-type (WT) males and had a significantly improved gut barrier function in old age. Several metabolic parameters were affected by both age and sex, but no genotype differences were detected. Neither male nor female Polr3b+/− mice were long-lived compared to WT controls. Overall, we find no evidence that a reduced Pol III activity extends mouse lifespan but we do find some potential organ- and sex-specific benefits for old-age health

Strain-specific metabolic responses to long-term caloric restriction in female ILSXISS recombinant inbred mice

The role that genetic background may play in the responsiveness of organisms to interventions such as caloric restriction (CR) is underappreciated but potentially important. We investigated genetic background on a suite of metabolic parameters in female recombinant inbred ILSXISS mouse strains previously reported to show divergent lifespan responses to 40% CR (TejJ89-lifespan extension; TejJ48-lifespan unaffected; TejJ114-lifespan shortening). Body mass was reduced across all strains following 10 months of 40% CR, although this loss (relative to ad libitum controls) was greater in TejJ114 relative to the other strains. Gonadal white adipose tissue (gWAT) mass was similarly reduced across all strains following 40% CR, but brown adipose tissue (BAT) mass increased only in strains TejJ89 and TejJ48. Surprisingly, glucose tolerance was improved by CR only in TejJ114, while strains TejJ89 and TejJ114 were relatively hyperinsulinemic following CR relative to their AL controls. We subsequently undertook an unbiased metabolomic approach in gWAT and BAT tissue from strains TejJ89 and TejJ114 mice under AL and 40% CR. gWAT from TejJ89 showed a significant reduction in several long chain unsaturated fatty acids following 40% CR, but gWAT from TejJ114 appeared relatively unresponsive to CR, with far fewer metabolites changing. Phosphatidylethanoloamine lipids within the BAT were typically elevated in TejJ89 following CR, while some phosphatidylglycerol lipids were decreased. However, BAT from strain TejJ114 again appeared unresponsive to CR. These data highlight strain-specific metabolic differences exist in ILSXISS mice following CR. We suggest that precisely how different fat depots respond dynamically to CR may be an important factor in the variable longevity under CR observed in these mice

Treatment patterns and frequency of key outcomes in acute severe asthma in children: a Paediatric Research in Emergency Departments International Collaborative (PREDICT) multicentre cohort study

Rationale Severe acute paediatric asthma may require treatment escalation beyond systemic corticosteroids, inhaled bronchodilators and low-flow oxygen. Current large asthma datasets report parenteral therapy only. Objectives To identify the use and type of escalation of treatment in children presenting to hospital with acute severe asthma. Methods Retrospective cohort study of children with an emergency department diagnosis of asthma or wheeze at 18 Australian and New Zealand hospitals. The main outcomes were use and type of escalation treatment (defined as any of intensive care unit admission, nebulised magnesium, respiratory support or parenteral bronchodilator treatment) and hospital length of stay (LOS). Measurements and main results Of 14 029 children (median age 3 (IQR 1–3) years; 62.9% male), 1020 (7.3%, 95% CI 6.9% to 7.7%) had treatment escalation. Children with treatment escalation had a longer LOS (44.2 hours, IQR 27.3–63.2 hours) than children without escalation 6.7 hours, IQR 3.5–16.3 hours; p<0.001). The most common treatment escalations were respiratory support alone (400; 2.9%, 95% CI 2.6% to 3.1%), parenteral bronchodilator treatment alone (380; 2.7%, 95% CI 2.5% to 3.0%) and both respiratory support and parenteral bronchodilator treatment (209; 1.5%, 95% CI 1.3% to 1.7%). Respiratory support was predominantly nasal high-flow therapy (99.0%). The most common intravenous medication regimens were: magnesium alone (50.4%), magnesium and aminophylline (24.6%) and magnesium and salbutamol (10.0%). Conclusions Overall, 7.3% children with acute severe asthma received some form of escalated treatment, with 4.2% receiving parenteral bronchodilators and 4.3% respiratory support. There is wide variation treatment escalation

The sublime and the spectator: Writing the landscape from Vernet to "Vineland".

This thesis analyzes Denis Diderot's Salons, art-critical writings by Charles Baudelaire, Thomas Pynchon's Vineland, and aesthetic theory by Jean-Francois Lyotard to arrive at a theory of landscape as a narrative response to visual phenomena, with specific reference to landscape as a painterly genre and as a genre of narrative description. I examine Baudelaire's use of the urban landscape of his day in the Salons and Spleen de Paris, and Pynchon's use of the mediated and media-influenced postmodern landscape of northern California. The dissertation traces the lineage of Lyotard's thought back to Diderot, demonstrating for the first time a strong link between the philosophies of Lyotard and Diderot in their theories of spectatorship and the sublime. Diderot can be shown not only to anticipate Lyotard, but in ways to look beyond him, thus implying a critique of Lyotardian aesthetics. I read the section on Vernet in the Salon de 1767 as a precursor of Lyotard's "Scapeland" in its displacement of the reader/spectator and in its purposeful confusion of the categories of painting and viewer, of object and viewing or perceiving subject. A similar subversion of these categories takes place in the writing of Baudelaire, particularly in Le spleen de Paris and in his analysis of the tableaux parisiens of Charles Meryon. Whereas in Diderot the visual medium of painting acts as a springboard for a narrative gesture I am calling landscape, in Pynchon's Vineland film and television are the genres within a genre that produce this narrative effect. Where Diderot uses the language of the Burkean sublime, Vineland evokes the postmodern sublime as theorized by Jameson, where individuals face a vast world interconnected by technology and impossible to cognize by the individual experiencing subject. A reading of the phenomenology of Lyotard's Pompidou Center exhibition "Les Immateriaux" in the final chapter of my dissertation investigates the institution of the postmodern museum, again relating it back to the spatial practice of Diderot's Salons.Ph.D.Comparative LiteratureUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/104688/1/9542936.pdfDescription of 9542936.pdf : Restricted to UM users only