Transcriptomic and proteomic analysis of mouse radiation-induced acute myeloid leukaemia (AML)

Badie, Christophe; Blachowicz, Agnieszka; Barjaktarović, Žarko; Finnon, Rosemary; Michaux, Arlette; Sarioglu, Hakan; Brown, Natalie; Manning, Grainne; Benotmane, Mohammed Abderrafi; Tapio, Soile; Polańska, Joanna; Bouffler, Simon

doi:10.18632/oncotarget.9626

Cited by 7 publications

(5 citation statements)

References 56 publications

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“…The association of IL7 gene and leukemia is mentioned in [61] and [62]. Furthermore, IL7 gene is associated with leukemia related KEGG pathways such as (hsa04630) Jak‐STAT signaling pathway ( p ‐value=4.50E‐05) [71,72], (hsa04060) cytokine‐cytokine receptor interaction pathway ( p ‐value=1.76E‐14) [73], (hsa04151) PI3KAkt signaling pathway ( p ‐value=1.29E‐13) [74–76], and the leukemia disease related GO terms like GO:CCs of extracellular space (GO:0005615) ( p ‐value=1.49E‐33) [83], extracellular region (GO:0005576) ( p ‐value=3.91E‐07) [82], and GO:MF of cytokine activity (GO:0005125) ( p ‐value=1.51E‐10) [84]. Besides that, the PTK2 gene is connected with leukemia as mentioned in [3,68,69].…”

Section: Resultsmentioning

confidence: 99%

“…In Ref. [84], authors reported involvement of GO:MF of cytokine activity in leukemia. The association between the GO:CC of extracellular region and leukemia is found in [82].…”

Section: Resultsmentioning

confidence: 99%

“…(hsa04151) PI3KAkt signaling pathway (p-value = 1.29E-13) [74-76], and the leukemia disease related GO terms like GO:CCs of extracellular space (GO:0005615) (p-value = 1.49E-33) [83], extracellular region (GO:0005576) (p-value = 3.91E-07) [82], and GO:MF of cytokine activity (GO:0005125) (p-value = 1.51E-10) [84]. Besides that, the PTK2 gene is connected with leukemia as mentioned in [3,68,69].…”

Section: Sub-dataset Number Of Oncogenesmentioning

confidence: 99%

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Towards integrated oncogenic marker recognition through mutual information‐based statistically significant feature extraction: an association rule mining based study on cancer expression and methylation profiles

Mallik

Zhao

2017

Quant. Biol.

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Background Marker detection is an important task in complex disease studies. Here we provide an association rule mining (ARM) based approach for identifying integrated markers through mutual information (MI) based statistically significant feature extraction, and apply it to acute myeloid leukemia (AML) and prostate carcinoma (PC) gene expression and methylation profiles. Methods We first collect the genes having both expression and methylation values in AML as well as PC. Next, we run Jarque-Bera normality test on the expression/methylation data to divide the whole dataset into two parts: one that ollows normal distribution and the other that does not follow normal distribution. Thus, we have now four parts of the dataset: normally distributed expression data, normally distributed methylation data, non-normally distributed expression data, and non-normally distributed methylated data. A feature-extraction technique, “mRMR” is then utilized on each part. This results in a list of top-ranked genes. Next, we apply Welch t-test (parametric test) and Shrink t-test (non-parametric test) on the expression/methylation data for the top selected normally distributed genes and non-normally distributed genes, respectively. We then use a recent weighted ARM method, “RANWAR” to combine all/specific resultant genes to generate top oncogenic rules along with respective integrated markers. Finally, we perform literature search as well as KEGG pathway and Gene-Ontology (GO) analyses using Enrichr database for in silico validation of the prioritized oncogenes as the markers and labeling the markers as existing or novel. Results The novel markers of AML are {ABCB11↑∪KRT17↓} (i.e., ABCB11 as up-regulated, & KRT17 as down-regulated), and {AP1S1-∪KRT17↓∪NEIL2-∪DYDC1↓}) (i.e., AP1S1 and NEIL2 both as hypo-methylated, & KRT17 and DYDC1 both as down-regulated). The novel marker of PC is {UBIAD1¶∪APBA2‡∪C4orf31‡} (i.e., UBIAD1 as up-regulated and hypo-methylated, & APBA2 and C4orf31 both as down-regulated and hyper-methylated). Conclusion The identified novel markers might have critical roles in AML as well as PC. The approach can be applied to other complex disease.

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Section: Resultsmentioning

confidence: 99%

“…In Ref. [84], authors reported involvement of GO:MF of cytokine activity in leukemia. The association between the GO:CC of extracellular region and leukemia is found in [82].…”

Section: Resultsmentioning

confidence: 99%

Section: Sub-dataset Number Of Oncogenesmentioning

confidence: 99%

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Towards integrated oncogenic marker recognition through mutual information‐based statistically significant feature extraction: an association rule mining based study on cancer expression and methylation profiles

Mallik

Zhao

2017

Quant. Biol.

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“…The dysregulation of Jarid2 gene is observed during Kaposi sarcoma-associated herpesvirus infection and leads to cell transformation [ 79 ]. Metap2, on the other hand, is differentially expressed in cells derived from mice developing an acute murine leukemia [ 54 ]. Thus, all these data suggest that P50 could act on several signaling pathways leading to insensitivity to growth inhibitory signals.…”

Section: Discussionmentioning

confidence: 99%

Murine leukemia virus (MLV) P50 protein induces cell transformation via transcriptional regulatory function

Akkawi,

Feuillard,

Diaz

et al. 2023

Retrovirology

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Background The murine leukemia virus (MLV) has been a powerful model of pathogenesis for the discovery of genes involved in cancer. Its splice donor (SD’)-associated retroelement (SDARE) is important for infectivity and tumorigenesis, but the mechanism remains poorly characterized. Here, we show for the first time that P50 protein, which is produced from SDARE, acts as an accessory protein that transregulates transcription and induces cell transformation. Results By infecting cells with MLV particles containing SDARE transcript alone (lacking genomic RNA), we show that SDARE can spread to neighbouring cells as shown by the presence of P50 in infected cells. Furthermore, a role for P50 in cell transformation was demonstrated by CCK8, TUNEL and anchorage-independent growth assays. We identified the integrase domain of P50 as being responsible for transregulation of the MLV promoter using luciferase assay and RTqPCR with P50 deleted mutants. Transcriptomic analysis furthermore revealed that the expression of hundreds of cellular RNAs involved in cancerogenesis were deregulated in the presence of P50, suggesting that P50 induces carcinogenic processes via its transcriptional regulatory function. Conclusion We propose a novel SDARE-mediated mode of propagation of the P50 accessory protein in surrounding cells. Moreover, due to its transforming properties, P50 expression could lead to a cellular and tissue microenvironment that is conducive to cancer development.

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“…In conclusion, this first description of a mouse model of radiation leukemia where it is possible to track leukemogenic events over time from initial exposure to presentation of disease provides a basis from which to study additional factors modulating radiation leukemia incidence. For example, how predisposition in human or mouse, exposure to pathogens, inflammation or calorie restriction can modify mouse radiation leukemia incidence [9,10]. Are the Chr2 deletion and subsequent mutation events directly related to target cell-intrinsic events, or could microenvironment-derived diffusible factors or microvesicle mediation play a role?…”

Section: Tom Verbiest Simon Bouffler and Christophe Badiementioning

confidence: 99%

Untitled

2018

Oncotarget

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A clear association between radiation exposure and increased incidence of leukemia has been widely described [1]. Over the past decades, various investigations into the changes taking place in the haematopoietic system following initial radiation exposure to physical presentation of leukemia have been completed. Previously, mice had to be sacrificed for the studies and bone marrow cells fixed after which chromosomal aberrations such as interstitial chromosome 2 (Chr2) deletions and Sfpi1 (PU.1) loss could be assessed by FISH [2,3] or CGH [4], resulting in a substantial use of mice and a loss of valuable information as it did not allow longitudinal tracking of Chr2 deleted cells over time. Very recently, it has been reported that, using a specifically engineered CBA Sfpi1 mCh/GFP mouse model carrying a mCherry or GFP fluorescent marker located in the Chr2 minimal deleted region, interstitial Chr2 deletions could be detected for the first time in haematopoietic cells in vivo by longitudinal blood sampling. This allowed for tracking of Chr2-deleted cells over time and a continuous assessment of the changes following Chr2 deletions and the progression to overt radiation-induced acute myeloid leukemia (rAML) [5].Monthly blood sampling of whole body irradiated male CBA Sfpi1 mCh/GFP mice provided novel insights into leukemia progression and presentation following radiation exposure. Firstly, focusing on mCherry fluorescence loss in individual cells, it was observed that the percentage of mice with mCherry-clonal expansion in peripheral blood white blood cells increased with time and reached 100% at 21 months following radiation exposure. Interestingly, the phenotype of mCherry-clonal expansion changed over time: whereas at 12 months mice presented with mixed lineage mCherry-clonal expansion only, the percentage of mice with lymphoid mCherry-clonal expansion increased over time. Increased GFP expression following radiationinduced deletion of the Rosa26-mCherry construct was detected implying that Sfpi1 expression is autoregulated, and is in line with previous reports that both the proximal promotor of Sfpi1 and the URE have binding sites for Sfpi1 itself [6]. Only when Sfpi1 expression was no longer upregulated (i.e. detected as identical GFP levels in mCherry-cells compared to mCherry+ cells), changes in white blood cell size and granularity could be detected in the peripheral blood. These changes could always be detected about three weeks before the mouse presented with outward physical signs of AML. All but one male leukemia cases were categorized as myeloid leukemia with an average latency of 11 months between radiation exposure and rAML presentation (9% of male mice). The myeloid leukemias observed in this study were consistent with the two-hit model previously postulated [7]: firstly an interstitial chromosome 2 deletion occurs accompanied by loss of Sfpi1 and the Rosa26-mCherry or GFP construct, followed by a point mutation in the remaining Sfpi1 copy.The vast majority of leukemia induction experiments have been ...

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Transcriptomic and proteomic analysis of mouse radiation-induced acute myeloid leukaemia (AML)

Cited by 7 publications

References 56 publications

Towards integrated oncogenic marker recognition through mutual information‐based statistically significant feature extraction: an association rule mining based study on cancer expression and methylation profiles

Towards integrated oncogenic marker recognition through mutual information‐based statistically significant feature extraction: an association rule mining based study on cancer expression and methylation profiles

Murine leukemia virus (MLV) P50 protein induces cell transformation via transcriptional regulatory function

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