A Comprehensive Study of TP53 Mutations in Chronic Lymphocytic Leukemia: Analysis of 1,287 Diagnostic CLL Samples
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1 A Comprehensive Study of TP53 Mutations in Chronic Lymphocytic Leukemia: Analysis of 1,287 Diagnostic CLL Samples Sona Pekova, MD., PhD. Chambon Ltd., Laboratory for molecular diagnostics, Prague, Czech Republic , Konference DNA analýza X, Novotel Praha
2 TP53 The Guardian of the Genome (David Lane, 1992) mapped to 17p G1/S arrest vs apoptosis physiologically low level of TP53 activity of TP53 tightly regulated (MDM-2, ATM, ATR, p19arf )
3 Functional analysis of TP53 Genotype does not necessarily need to translate into phenotype FASAY Functional Analysis of Separated Alleles in Yeast in vitro test of the functional activity of TP53 DNA-binding domain color of transgenic yeast colonies indicates mutated or wild type TP53 allele
4 The principle of FASAY in vitro recombination of TP53 into GM yeasts p53 promotor Selection medium with low adenine Red colonies mut White colonies wt p53 respons promotor ADE2 pss16 p53 Red colonies are re-sequenced to identify clonal TP53 mutation
5 A. Detection of biologically relevant TP53 variants C277Y 60.1 % red colonies
6 B. Identification of small subclones with TP53 mutation E220R 27.5 % red colonies
7 C. Splicing TP53 variants delta ex6 TP53 splicing variant in CLL 45.3 % red colonies on FASAY Pekova et al., Leukemia Research, 2010
8
9 Bourdon et al., Genes Dev., 2005
10 Protein expression of the D ex6 TP53 variant Pekova et al., Leukemia Research, 2010
11 Pekova et al., Leukemia Research, 2010 In vitro growth properties of stabledex6 TP53 cell lines H1299 Dex6 H1299 mock
12 Growth curves of stable Dex6 TP53 and mock transfected H1299 cell lines Pekova et al., Leukemia Research, 2010
13 Pekova et al., Leukemia Research, 2010 Expression profiles of Dex6 TP53 and mock transfected H1299 cell lines Dex6 vs mock Affymetrix GeneChip Human Exon 1.0 ST array
14 Pekova et al., Leukemia Research, 2010 In vitro properties of the Dex6 TP53 variant: cyclins (A1, G1, G2, F, I, B2, A2, T2) matrix metalloproteinases serine proteases hyaluronidases inhibitors of caspases adhesion molecules molecules of intercellular matrix Accented proliferative phenotype, loss of intercellular contacts, defects of apoptosis
15 D. Identification of temperature-sensitive TP53 variants S127F
16 Mr. Brother and Mrs. Sister Case Pekova et al., Leukemia Research, 2010 FASAY: wild type p53 FASAY: 51.8% t.s. colonies
17 Back-tracking the t.s. variant R283C, cdna sequencing Pekova et al., Leukemia Research, 2010
18 Pekova et al., Leukemia Research, 2010
19 Site-directed mutagenesis/ Megaprimer Eco RI Eco RV C/T T T
20 Pekova et al., Leukemia Research, 2010
21 Pekova et al., Leukemia Research, 2010 Production of H1299 stable cell lines harboring temperature-sensitive TP53 variants
22 Pekova et al., Leukemia Research, 2010 Stable H1299 cell lines expressing temperature-sensitive variants of TP53 Temperature-sensitive TP53 variants V157F, A161T, S215I, V216M, Y234C resemble in vitro R175H Temperature-sensitive TP53 variants N235S, R283C, K320E, K320T resemble in vitro WT TP53
23 List of all TP53 mutations/variants identified in the study Table 1: List of all TP53 mutations/variants identified in the study. Temperature-sensitive variants are highlighted in blue. Mutation Nr. Mutation Nr. Mutation Nr. Mutation Nr. Mutation Nr. Mutation Nr. TP53 splicing variant Delta E68X 3 K164E 1 H214R 1 P250L 1 D281V 2 Ex6 16 W91X 1 Q167X 1 S215I 1 P250S 1 R282W 1 c.780_781insagt 1 K101E 1 V172A 1 V216M 1 I251V 1 R283C 7 c.559_560insg 1 P109I 1 V173A 2 R219I 1 I255T 2 T284S 1 c.782_783instat 1 R110L 2 R175H 2 Y220C 4 T256P 1 E286G 1 c.102_103insc 1 F113S 2 C176R 2 Y220H 1 E258G 1 K305M 1 Y126C 2 C176W 1 P222L 1 E258K 1 K320E 1 Y126H 1 P177L 1 S227P 1 D259G 2 K320T 1 K132N 2 H178R 1 H233R 4 D259S 1 L330P 1 Q136E 1 P178S 1 Y234C 5 G266R 1 c.302_del 1 A138V 1 H179L 1 Y234D 3 R267P 1 c.328_339del 1 K139R 2 H179R 4 Y234H 1 R267W 1 c.503_ 578del 1 C141Y 1 R181S 1 N235S 2 R273C 2 c.504_578del 1 Q144X 2 D186N 1 M237I 2 R273H 4 c.515_559del 1 W146X 1 G187D 1 N239D 1 R273S 1 c. 550_576del 1 P151S 1 L188P 1 S241C 1 C275G 1 c. 636del 1 P152L 1 P190H 1 M243T 1 C275Y 1 c.704_709del 1 P153L 1 P190S 1 G245D 1 A276V 1 c.716_736del 1 R156P 1 H193L 2 G245S 8 C277F 1 c.724_739del 1 V157F 2 H193R 2 N247D 1 C277Y 2 c.749_751del 1 V157G 1 L194P 1 R248Q 1 R280K 1 c.792_794del 1 A159P 2 R196X 1 R248W 8 R280P 1 c.828del 1 A161T 3 Y205C 1 R249S 3 R280T 1 c. 532_ 549del 1 TP53 splicing variant Y163H 2 R213X 1 R249W 1 D281G 1 Beta 30
24 Pekova et al., Leukemia Research, 2010 Summary 1,287 diagnostic CLL samples tested 18,4% of FASAY-corroborated TP53 mutations/variants Modes of TP53 inactivation diverse (point mutations, insertions, deletions, temperature-sensitive variants, aberrant splicing variants) Splicing variants might play biological role Temperature-sensitive TP53 variants V157F, A161T, S215I, V216M, Y234C resemble in vitro R175H Temperature-sensitive TP53 variants N235S, R283C, K320E, K320T resemble in vitro WT TP53
25 Thank you for your attention
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