Gene expression analysis of paediatric acute lymphoblastic leukaemia
ABSTRACT: We addressed the clinical significance and mechanisms behind in vitro cellular responses to ionising radiation (IR)-induced DNA double strand breaks in 74 paediatric ALL patients. We found an apoptosis-resistant response in 36% of patients and an apoptosis-sensitive response in the remaining 64% of leukaemias. Global gene expression profiling of 11 apoptosis-resistant and 11 apoptosis-sensitive ALLs revealed abnormal up-regulation of multiple pro-survival pathways in response to IR in apoptosis-resistant leukaemias and differential post-transcriptional activation of the PI3-Akt pathway was observed in representative resistant cases. It is possible that abnormal pro-survival responses to DNA damage provide one of the mechanisms of primary resistance in ALL . Keywords: Gene expression profiling; response to irradiation Overall design: Twenty two B-precursor ALL tumours (11 responsive to IR-induced DNA damage and 11 resistant) were analysed before and 8 hours after exposure to 5 Gy IR, using the Affymetrix HG_U133A (GPL96) platform.
INSTRUMENT(S): [HG-U133A] Affymetrix Human Genome U133A Array
Project description:We addressed the clinical significance and mechanisms behind in vitro cellular responses to ionising radiation (IR)-induced DNA double strand breaks in 74 paediatric ALL patients. We found an apoptosis-resistant response in 36% of patients and an apoptosis-sensitive response in the remaining 64% of leukaemias. Global gene expression profiling of 11 apoptosis-resistant and 11 apoptosis-sensitive ALLs revealed abnormal up-regulation of multiple pro-survival pathways in response to IR in apoptosis-resistant leukaemias and differential post-transcriptional activation of the PI3-Akt pathway was observed in representative resistant cases. It is possible that abnormal pro-survival responses to DNA damage provide one of the mechanisms of primary resistance in ALL . Experiment Overall Design: Twenty two B-precursor ALL tumours (11 responsive to IR-induced DNA damage and 11 resistant) were analysed before and 8 hours after exposure to 5 Gy IR, using the Affymetrix HG_U133A (GPL96) platform.
Project description:Treatment with ionizing irradiation (IR) may lead to accumulation of tumor-infiltrating T regulatory (Treg) cells and subsequent tumor resistance to radiotherapy. Here we focused on the contribution of Langerhans cells (LCs) to this phenomenon because of their unique ability to resist depletion by high-dose IR. We found that LCs resisted apoptosis and rapidly repaired DNA damage post-IR. Particularly, we found that p21 was overexpressed in LCs, and that p21-deficient LCs underwent apoptosis and accumulated DNA damage following IR treatment. Wild-type, but not p21-deficient, LCs upregulated major histocompatibility complex class II molecules, migrated to the draining lymph nodes and increased Treg cell numbers upon exposure to IR. These findings suggest a means for manipulating LC IR-resistance to increase cutaneous tumor response to radiotherapy. See above Cells were purified by flow cytometry and pooled until >10,000 cells/sample. At least 2 replicates of each sample were submitted.
Project description:The tumor suppressor p53 is mainly involved in the transcriptional regulation of a large number of growth-arrest- and apoptosis-related genes. However, a clear understanding of which factor/s influences the choice between these two opposing p53- dependent outcomes remains largely elusive. We have previously described that in response to DNA damage, the RNA polymerase II binding protein Che-1/AATF transcriptionally activates p53. Here, we show that Che-1 binds directly p53. This interaction essentially occurs in the first hours of DNA damage, whereas it is lost when cells undergo to apoptosis in response to post-transcriptional modifications. Moreover, Che-1 sits in a ternary complex with p53 and the oncosuppressor Brca1. Accordingly, our analysis of genome-wide chromatin occupancy by p53 revealed that p53/Che1 interaction results in preferential transactivation of growth-arrest p53 target genes over its pro-apoptotic target genes. Notably, exposure of Che-1+/- mice to ionizing radiations resulted in enhanced apoptosis of thymocytes, compared to wild-type mice. These results confirm Che-1 as an important regulator of p53 activity and suggest Che-1 to be a promising yet attractive drug target for cancer therapy. Overall design: ChIP-Seq for p53 in control (DNA damage, IR) and Che-1 depleted Hct116 cells
Project description:Dunster2014 - WBC Interactions (Model1)
This is a sub-model of a three-step
inflammatory response modelling study. The model includes distinct
populations of white blood cells namely, macrophages and active and
apoptotic neutrophil populations. Neutrophil apoptosis rate is
predicted to be crucial for the qualitative nature of the
This model is described in the article:
The resolution of
inflammation: a mathematical model of neutrophil and macrophage
Dunster JL, Byrne HM, King JR.
Bull. Math. Biol. 2014 Aug; 76(8):
There is growing interest in inflammation due to its
involvement in many diverse medical conditions, including
Alzheimer's disease, cancer, arthritis and asthma. The
traditional view that resolution of inflammation is a passive
process is now being superceded by an alternative hypothesis
whereby its resolution is an active, anti-inflammatory process
that can be manipulated therapeutically. This shift in mindset
has stimulated a resurgence of interest in the biological
mechanisms by which inflammation resolves. The
anti-inflammatory processes central to the resolution of
inflammation revolve around macrophages and are closely related
to pro-inflammatory processes mediated by neutrophils and their
ability to damage healthy tissue. We develop a spatially
averaged model of inflammation centring on its resolution,
accounting for populations of neutrophils and macrophages and
incorporating both pro- and anti-inflammatory processes. Our
ordinary differential equation model exhibits two outcomes that
we relate to healthy and unhealthy states. We use bifurcation
analysis to investigate how variation in the system parameters
affects its outcome. We find that therapeutic manipulation of
the rate of macrophage phagocytosis can aid in resolving
inflammation but success is critically dependent on the rate of
neutrophil apoptosis. Indeed our model predicts that an
effective treatment protocol would take a dual approach,
targeting macrophage phagocytosis alongside neutrophil
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Project description:We use mice containing a gene trap in the first intron of the Rest gene, which effectively eliminates transcription from all coding exons, to prematurely remove REST from neural progenitors. We find catastrophic DNA damage that occurs during S-phase of the cell cycle and concominant with activation of p53 pro-apoptotic sgnalling, with consequences including abnormal chromosome separation, apoptosis, and smaller brains. extract RNA from E12.5 brain in quadriplicates, compare gene expression profile between Gene Trap REST knockout mice and control littermates
Project description:The DNA damage response network modulates a wide array of signaling pathways, including DNA repair, cell cycle checkpoints, apoptotic pathways and numerous stress signals. The ATM protein kinase, functionally missing in patients with the human genetic disorder ataxia-telangiectasia (A-T), is a master regulator of this network when the inducing DNA lesions are double strand breaks. The ATM gene is also frequently mutated in sporadic cancers of lymphoid origin. Here, we applied a functional genomics approach that combines gene expression profiling and computational promoter analysis to obtain global dissection of the transcriptional response to ionizing radiation (IR) in murine lymphoid tissue. Cluster analysis revealed six major expression patterns in the data. Prominent among them was a gene cluster that contained dozens of genes whose response to irradiation was Atm-dependent. Computational analysis identified significant enrichment of the binding site signatures of the transcription factors NF-kB and p53 among promoters of these genes, pointing to the major role of these two transcription factors in mediating the Atm-dependent transcriptional response in the irradiated lymphoid tissue. Examination of the response showed that pro- and anti-apoptotic signals were simultaneously induced, with the pro-apoptotic pathway mediated by p53, and the pro-survival pathway by NF-kB. These findings further elucidate the molecular network induced by IR and have implications for cancer management as they suggest that a combined treatment that restores the p53-mediated apoptotic arm while blocking the NF-kB-mediated pro-survival arm could be most successful in increasing the radiosensitivity of lymphoid tumors.
Project description:This a model from the article:
Minimum criteria for DNA damage-induced phase advances in circadian rhythms.
Hong CI, Zámborszky J, Csikász-Nagy A.
PLoS Comput Biol. 2009 May;5(5):e1000384.
Robust oscillatory behaviors are common features of circadian and cell cycle rhythms. These cyclic processes, however, behave distinctively in terms of their periods and phases in response to external influences such as light, temperature, nutrients, etc. Nevertheless, several links have been found between these two oscillators. Cell division cycles gated by the circadian clock have been observed since the late 1950s. On the other hand, ionizing radiation (IR) treatments cause cells to undergo a DNA damage response, which leads to phase shifts (mostly advances) in circadian rhythms. Circadian gating of the cell cycle can be attributed to the cell cycle inhibitor kinase Wee1 (which is regulated by the heterodimeric circadian clock transcription factor, BMAL1/CLK), and possibly in conjunction with other cell cycle components that are known to be regulated by the circadian clock (i.e., c-Myc and cyclin D1). It has also been shown that DNA damage-induced activation of the cell cycle regulator, Chk2, leads to phosphorylation and destruction of a circadian clock component (i.e., PER1 in Mus or FRQ in Neurospora crassa). However, the molecular mechanism underlying how DNA damage causes predominantly phase advances in the circadian clock remains unknown. In order to address this question, we employ mathematical modeling to simulate different phase response curves (PRCs) from either dexamethasone (Dex) or IR treatment experiments. Dex is known to synchronize circadian rhythms in cell culture and may generate both phase advances and delays. We observe unique phase responses with minimum delays of the circadian clock upon DNA damage when two criteria are met: (1) existence of an autocatalytic positive feedback mechanism in addition to the time-delayed negative feedback loop in the clock system and (2) Chk2-dependent phosphorylation and degradation of PERs that are not bound to BMAL1/CLK.
The original xpp file of the model is available as a supplement of the article (Text S1).
Project description:The Mre11 complex (Mre11, Rad50, and Nbs1) and Chk2 have been implicated in the DNA damage response, an inducible process required for the suppression of malignancy. The Mre11 complex is predominantly required for repair and checkpoint activation in S phase, while Chk2 governs apoptosis. We examined the relationship between the Mre11 complex and Chk2 in the DNA damage response via the establishment of Nbs1∆B/∆B Chk2-/- and Mre11ATLD1/ATLD1 Chk2-/- mice. Chk2 deficiency did not modify the checkpoint defects or chromosomal instability of Mre11 complex mutants; however, the double mutant mice exhibited synergistic defects in DNA damage-induced p53 regulation and apoptosis. Nbs1∆B/∆B Chk2-/- and Mre11ATLD1/ATLD1 Chk2-/- mice were also predisposed to tumors. In contrast, DNA-PKcs deficient mice, in which G1-specific chromosome breaks are present, did not exhibit synergy with Chk2-/- mutants. These data suggest that Chk2 suppresses the oncogenic potential of DNA damage arising during S and G2 phases of the cell cycle. Experiment Overall Design: Thymocytes from Wild type (Wt), Atm-/- and Chk2-/- mice were exposed to mock 5 Gy radiation (IR). The RNA was harvested 8 hours post treatment.
Project description:This a model from the article:
Computational insights on the competing effects of nitric oxide in regulating
Bagci EZ, Vodovotz Y, Billiar TR, Ermentrout B, Bahar I. PLoS One
2008 May 28;3(5):e2249 18509469
Despite the establishment of the important role of nitric oxide (NO) on
apoptosis, a molecular-level understanding of the origin of its dichotomous pro-
and anti-apoptotic effects has been elusive. We propose a new mathematical model
for simulating the effects of nitric oxide (NO) on apoptosis. The new model
integrates mitochondria-dependent apoptotic pathways with NO-related reactions,
to gain insights into the regulatory effect of the reactive NO species N(2)O(3),
non-heme iron nitrosyl species (FeL(n)NO), and peroxynitrite (ONOO(-)). The
biochemical pathways of apoptosis coupled with NO-related reactions are
described by ordinary differential equations using mass-action kinetics. In the
absence of NO, the model predicts either cell survival or apoptosis (a bistable
behavior) with shifts in the onset time of apoptotic response depending on the
strength of extracellular stimuli. Computations demonstrate that the relative
concentrations of anti- and pro-apoptotic reactive NO species, and their
interplay with glutathione, determine the net anti- or pro-apoptotic effects at
long time points. Interestingly, transient effects on apoptosis are also
observed in these simulations, the duration of which may reach up to hours,
despite the eventual convergence to an anti-apoptotic state. Our computations
point to the importance of precise timing of NO production and external
stimulation in determining the eventual pro- or anti-apoptotic role of NO.
This model was taken from the CellML repository
and automatically converted to SBML.
The original model was:
Bagci EZ, Vodovotz Y, Billiar TR, Ermentrout B, Bahar I. (2008) - version=1.0
The original CellML model was created by:
The University of Auckland
This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2011 The BioModels.net Team.
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To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.