Shape of the dose-response for Cancer Christophe Badie Cancer - - PowerPoint PPT Presentation
INTEGRATED SYSTEMS LEVEL ANALYSIS OF MYELOID LEUKAEMOGENESIS AND EVALUATION OF THE MOLECULAR ALTERATIONS OF ANTIGENIC T-CELL RECEPTOR REPERTOIRE FOLLOWING X-IRRADIATION WP5 Shape of the dose-response for Cancer Christophe Badie Cancer Genetics
WP5 Shape of the dose-response for Cancer
INTEGRATED SYSTEMS LEVEL ANALYSIS OF MYELOID LEUKAEMOGENESIS AND EVALUATION OF THE MOLECULAR ALTERATIONS OF ANTIGENIC T-CELL RECEPTOR REPERTOIRE FOLLOWING X-IRRADIATION
Christophe Badie Cancer Genetics and Cytogenetics group Radiation Effects Department Centre for Radiation, Chemical & Environmental Hazards Public Health England United Kingdom
the TCR (antigenic T cell receptor) gene repertoire in low dose irradiated mice
Primary rAML material (infiltrated spleen tissues) rAML cell-lines*
*Derived from the primary tumours studied independently
Global gene expression
Affymetrix GeneChip arrays
Proteomic alterations
Isotope Coded Protein Label (ICPL)
digested and analysed by mass spectrometry
control cell population*
*BM sorted non committed progenitor cells (Lin-)
Primary Cell-lines Lin- cells
Differential modulation between primary rAML and cell lines
Common proteins within primary rAML
Common proteins within rAML cell lines
Proteins involved in translation (Ribosomal)
Eukaryotic translation initiation factor 2 (eIF2) is central to the onset of protein synthesis
Proteins involved in glucose metabolism
Primary cells Cell lines
p53 relative expression
0.0 0.1 0.2 0.3 0.4
c MLP3 RF12 RF24
* * * * C MLP3 RF12 RF26
C MLP3 RF12 RF26
P53 actin
C MLP3 RF12 RF26
P53 actin
Cell lines Primary cells * * *
C MLP3 RF12 RF26
* * *
C MLP3 RF12 RF26
C MLP3 RF12 RF26 c-myc actin C MLP3 RF12 RF26 C-myc actin
Protein synthesis
Cell lines Primary cells * * *
C MLP3 RF12 RF26
RPS16 relative expression
0.0 0.1 0.2 0.3 0.4
c MLP3 RF12 RF24
* *
c MLP3 RF12 RF24
RPS16 actin RPS16 actin
* * C MLP3 RF12 RF26 Thrombospondin actin * * * C MLP3 RF12 RF26 Cell lines Primary cells Thrombospondin actin
Angiogenesis(-) -Immune regulation - Apoptosis
Primary vs. control - genes
Upregulated genes Downregulated genes Differentially expressed genes
Number of common genes and Sørensen-Dice index for deregulated genes Compared samples # common upregulated genes Sørensen- Dice index MLP3 and RF12 and RF26 2526 0.5860 MLP3 and RF12 2982 0.6851 MLP3 and RF26 3014 0.6824 RF12 and RF26 3214 0.7722 Number of common genes and Sørensen- Dice index for upregulated genes Number of common genes and Sørensen- Dice index for downregulated genes Compared samples Number of common deregulated genes Sørensen-Dice similarity index for genes MLP3 and RF12 and RF26 5521 0.5549 MLP3 and RF12 6657 0.6376 MLP3 and RF26 6399 0.6934 RF12 and RF26 7347 0.7218
Primary vs. control - genes
Compared samples # common downregulated genes Sørensen- Dice index MLP3 and RF12 and RF26 2995 0.5114 MLP3 and RF12 3675 0.5826 MLP3 and RF26 3385 0.6750 RF12 and RF26 4133 0.6614
Primary vs. control - proteins
Differentially expressed proteins Upregulated proteins Downregulated proteins
Number of common genes and Sørensen-Dice index for deregulated proteins Compared samples # common upregulated proteins Sørensen- Dice index MLP3 and RF12 and RF26 1 0.0162 MLP3 and RF12 6 0.1000 MLP3 and RF26 1 0.0182 RF12 and RF26 44 0.6286 Number of common genes and Sørensen- Dice index for upregulated proteins Number of common genes and Sørensen- Dice index for downregulated proteins Compared samples Number of common deregulated proteins Sørensen-Dice similarity index for proteins MLP3 and RF12 and RF26 3 0.0304 MLP3 and RF12 11 0.1134 MLP3 and RF26 4 0.0454 RF12 and RF26 85 0.7658
Primary vs. control - proteins
Compared samples # common downregulated proteins Sørensen- Dice index MLP3 and RF12 and RF26 2 0.0337 MLP3 and RF12 5 0.0789 MLP3 and RF26 3 0.0508 RF12 and RF26 41 0.7387
Cell line vs. control - genes
Upregulated genes Downregulated genes Differentially expressed genes
Number of common genes and Sørensen-Dice index for deregulated genes Compared samples # common upregulated genes Sørensen- Dice index MLP3 and RF12 and RF26 2713 0.5392 MLP3 and RF12 3476 0.7047 MLP3 and RF26 3408 0.6566 RF12 and RF26 3270 0.6576 Number of common genes and Sørensen- Dice index for upregulated genes Number of common genes and Sørensen- Dice index for downregulated genes Compared samples Number of common deregulated genes Sørensen-Dice similarity index for genes MLP3 and RF12 and RF26 5220 0.5870 MLP3 and RF12 6590 0.7391 MLP3 and RF26 6338 0.7059 RF12 and RF26 6255 0.7123
Cell line vs. control - genes
Compared samples # common downregulated genes Sørensen- Dice index MLP3 and RF12 and RF26 2507 0.5988 MLP3 and RF12 3114 0.7427 MLP3 and RF26 2930 0.7050 RF12 and RF26 2985 0.7087
Cell line vs. control - proteins
Differentially expressed proteins Upregulated proteins Downregulated proteins
Number of common genes and Sørensen-Dice index for deregulated proteins Compared samples # common upregulated proteins Sørensen- Dice index MLP3 and RF12 and RF26 28 0.4667 MLP3 and RF12 39 0.6047 MLP3 and RF26 32 0.5664 RF12 and RF26 32 0.5424 Number of common genes and Sørensen- Dice index for upregulated proteins Number of common genes and Sørensen- Dice index for downregulated proteins Compared samples Number of common deregulated proteins Sørensen-Dice similarity index for proteins MLP3 and RF12 and RF26 55 0.4508 MLP3 and RF12 76 0.6056 MLP3 and RF26 65 0.5830 RF12 and RF26 75 0.5814
Cell line vs. control - proteins
Compared samples # common downregulated proteins Sørensen- Dice index MLP3 and RF12 and RF26 27 0.4197 MLP3 and RF12 37 0.5920 MLP3 and RF26 33 0.5690 RF12 and RF26 43 0.5931
Primary vs. cell line - genes
Upregulated genes Downregulated genes Differentially expressed genes
Number of common genes and Sørensen-Dice index for deregulated genes Compared samples # common upregulated genes Sørensen- Dice index MLP3 and RF12 and RF26 2007 0.4205 MLP3 and RF12 2584 0.5724 MLP3 and RF26 2854 0.5774 RF12 and RF26 3053 0.6279 Number of common genes and Sørensen- Dice index for upregulated genes Number of common genes and Sørensen- Dice index for downregulated genes Compared samples Number of common deregulated genes Sørensen-Dice similarity index for genes MLP3 and RF12 and RF26 5034 0.4141 MLP3 and RF12 7096 0.5766 MLP3 and RF26 6720 0.5960 RF12 and RF26 8582 0.6659
Primary vs. cell line - genes
Compared samples # common downregulated genes Sørensen- Dice index MLP3 and RF12 and RF26 3027 0.3629 MLP3 and RF12 4512 0.5337 MLP3 and RF26 3866 0.5219 RF12 and RF26 5529 0.6037
Primary vs. cell line - proteins
Differentially expressed proteins Upregulated proteins Downregulated proteins
Number of common genes and Sørensen-Dice index for deregulated proteins Compared samples # common upregulated proteins Sørensen- Dice index MLP3 and RF12 and RF26 18 0.2000 MLP3 and RF12 28 0.3256 MLP3 and RF26 29 0.3580 RF12 and RF26 68 0.6602 Number of common genes and Sørensen- Dice index for upregulated proteins Number of common genes and Sørensen- Dice index for downregulated proteins Compared samples Number of common deregulated proteins Sørensen-Dice similarity index for proteins MLP3 and RF12 and RF26 40 0.2532 MLP3 and RF12 66 0.4125 MLP3 and RF26 52 0.3599 RF12 and RF26 124 0.7316
Primary vs. cell line - proteins
Compared samples # common downregulated proteins Sørensen- Dice index MLP3 and RF12 and RF26 22 0.2558 MLP3 and RF12 38 0.4000 MLP3 and RF26 23 0.2857 RF12 and RF26 56 0.6788
transcriptomics and proteomics
key drivers of leukaemogenesis as use of in vitro cultured materials could be misleading
pathways associated with radiation-induced leukaemia
What are the effects of low dose exposure on immune cells development? Analysis of T lymphocyte diversity
Dranoff, Nature Reviews Cancer,2004
Innate Immunity Adaptive Immunity
Gitlin AD and Nussenzweig MC Nature 2015
The theoritical abTCR: more than 1014 different possibilities
Selections of T cell repertoire
Attaf M. et al. CEI 2015
Can radiation exposure perturb the system and increase genetic instability in lymphocytes?
Each lymphocyte express a unique antigenic receptor
V(D)J recombination: T cell receptor genes
Attaf M. et al. CEI 2015 Keener AB. Nature Med. 2015
Equitability:
S: number of classes
g: Comparison of the frequencies of V/D/J genes between groups (30 mice, 16876120 total, 512938 unique sequences) (preliminary results)
Effects of acute low dose radiation on the T cell receptor repertoire in vivo
Paul Finnon, Rosemary Finnon, Natalie Brown, Simon Bouffler PHE, United Kingdom Rafi Benotmane SCK•CEN, Belgium Zarko Barjaktarovic, Soile Tapio HMGU, Germany Agnieszka Blachowicz, Justyna Kotas and Joanna Polanska Silesian University of Technology, Poland Serge Candeias CEA, France
25-29th August 2019 Manchester Central Manchester UK