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Deletions linked to TP53 loss drive cancer through p53-independent mechanisms

Abstract

Mutations disabling the TP53 tumour suppressor gene represent the most frequent events in human cancer and typically occur through a two-hit mechanism involving a missense mutation in one allele and a ‘loss of heterozygosity’ deletion encompassing the other. While TP53 missense mutations can also contribute gain-of-function activities that impact tumour progression, it remains unclear whether the deletion event, which frequently includes many genes, impacts tumorigenesis beyond TP53 loss alone. Here we show that somatic heterozygous deletion of mouse chromosome 11B3, a 4-megabase region syntenic to human 17p13.1, produces a greater effect on lymphoma and leukaemia development than Trp53 deletion. Mechanistically, the effect of 11B3 loss on tumorigenesis involves co-deleted genes such as Eif5a and Alox15b (also known as Alox8), the suppression of which cooperates with Trp53 loss to produce more aggressive disease. Our results imply that the selective advantage produced by human chromosome 17p deletion reflects the combined impact of TP53 loss and the reduced dosage of linked tumour suppressor genes.

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Figure 1: The frequency, scope, and prognostic value of chromosome 17p alterations in human cancers.
Figure 2: A mouse model of human 17p13.1 deletion accelerates lymphoma development.
Figure 3: 11B3 deletion can accelerate lymphomagenesis through p53-independent mechanisms.
Figure 4: 11B3 encodes multiple genes whose attenuation cooperates with Trp53 loss to drive lymphoma.
Figure 5: Chromosome 11B3 deletion acts beyond Trp53 loss to drive myeloid leukaemia.

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Gene Expression Omnibus

Data deposits

17p13 shRNA library specification is provided in Supplementary Information. The raw and analysed RNA sequence data have been deposited in the Gene Expression Omnibus under accession number GSE69654.

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Acknowledgements

We thank J. P. Morris, L. Dow, D. Tschaharganeh, E. Manchado, T. Kitzing, E. Loizou and other Lowe laboratory members for their critical discussions and technical help, C. J. Sherr for invaluable advice, L. Dai and M. Tang for liquid chromatography–mass spectrometry support, and Y. Park and S. Kim for their help in constructing the 11B3 mouse model. This work was supported by a programme project and an R01 grant from the National Cancer Institute (S.W.L.), a Center grant for Cancer Target Discovery and Development (S.W.L.), and a Memorial Sloan Kettering Cancer Center Support Grant. Y.L. was supported by an American Association for Cancer Research Millennium Fellowship in Lymphoma Research. C.C. is supported by the Thousand Young Talents Plan and the National Natural Science Foundation of China (81522003, 81570150). S.W.L. is the Geoffrey Beene Chair for Cancer Biology and a Howard Hughes Medical Institute Investigator.

Author information

Authors and Affiliations

Authors

Contributions

Y.L. and S.W.L. designed the experiments. Y.L., C.C., S.A., Z.X. and L.C. performed the experiments. Y.L., C.C., Z.X., T.N. and S.W.L. analysed data. Y.L., C.S. and A.A.M. designed the 11B3 model, Y.L., C.S., J.G., B.B., E.R.K., T.B., B.S., T.N., Q.W., N.S. and R.L.L. contributed to the human cancer genomic analysis. Y.L., C.C., C.D.R. and S.W.L. organized data and wrote the manuscript.

Corresponding author

Correspondence to Scott W. Lowe.

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The authors declare no competing financial interests.

Extended data figures and tables

Extended Data Figure 1 The frequency and prognostic impact of chromosome 17p deletion with the copy number loss identified by GISTIC.

a, The ratio of chromosome-copy-number-altered cases within TP53-mutated cases compared to those within wild-type cases. TP53 mutations were statistically correlated with 17p loss (P < 0.001) but also other copy number events (P < 0.001). b, Peaks of copy number loss identified by the GISTIC algorithm in NHL or AML. x axis, GISTIC q value; y axis, chromosome. q < 0.25 is considered as significant. c, Overall survival of human diffuse large B-cell lymphoma (DLBCL) patients with chromosome 17p deletion is significantly shortened compared to those with no 17p copy number variants, as annotated from the Gene Expression Omnibus GSE34171 series. *P < 0.05 (log-rank test).

Extended Data Figure 2 Generation of a chromosome 11B3 conditional knockout mouse.

a, Top, strategy to introduce 5′ HPRT gene and loxP site telomeric to Sco1 on chromosome 11B3 with MICER clone MHPN91j22. Bottom, Southern blot demonstrating correct targeting of the derived ES cells. st, single-targeted allele; wt, wild-type. Blue arrowheads denote loxP sites. b, Top, strategy to introduce 3′ HPRT gene and loxP site centromeric to Alox12 on chromosome 11B3 with MICER clone MHPP248j19. Bottom, Southern blot demonstrating correct targeting of the derived ES cells. dt, double-targeted allele. c, Top, diagram showing the expected PCR results and drug-resistance phenotypes of doubly targeted ES cells harbouring loxP sites in cis versus in trans. GR, G418 (neomycin) resistance; PR, puromycin resistance; HR, HAT resistance. df, deleted allele; dp, duplicated allele. Green bar indicates the PCR product location and length. Bottom, PCR results show different ES cell clones generated in a and b.

Extended Data Figure 3 11B3 recombination and lymphomagenesis in Eu-Myc model.

a, The extent of 11B3 deletion in peripheral blood cells, as determined by semi-quantitative PCR, in 11B3fl/+ mice crossed to Cd19-cre (left), Mx1-cre (middle) or Vav1-cre (right). Genomic DNA from 11B3+/Δ ES cells was mixed with 11B3fl/+ cells at different ratios (5% or 20%) as a standard. For Mx1-cre, 6–8-week-old mice were treated with polyinosinic:polycytidylic acid (poly(I:C)) (15 mg kg−1 every other day, 7 times) by intraperitoneal injection. b, Partial 11B3 deletion in Vav1-cre;11B3fl/+ pre-B cells as determined by semi-quantitative PCR, indicating incomplete recombination. c, Complete Trp53fl/+ recombination in Vav1-cre;Trp53fl/+ pre-B cells as determined by PCR. d, Tumour-free survival of Eμ-Myc;Vav1-cre;Trp53fl/+ (n = 9), Eμ-Myc;Vav1-cre;11B3fl/+ (n = 12) and Eμ-Myc;Vav1-cre (n = 6) mice shows that 11B3-deleted tumours have longer tumour latency than Trp53-loss-only controls. ***P < 0.001 (log-rank test).

Extended Data Figure 4 Charaterization of 11B3-deleted lymphoma.

a, Immunophenotypes of B220+ Eμ-Myc lymphomas generated from Vav1-cre;p53fl/+ or Vav1-cre;11B3fl/+. 11B3-deleted lymphomas were either IgMIgD or IgM+IgD+ while all the Trp53-null lymphomas were IgMIgD. b, Haematoxylin and eosin (H&E) stainings of lymph node, spleen and liver of moribund, lymphoma-bearing mice originating from Eμ-Myc;Vav1-cre;11B3fl/+ or Eμ-Myc;Vav1-cre;Trp53fl/+ genotypes. Scale bar, 50 μm. c, 11B3-deleted lymphoma cells isolated from enlarged lymph nodes are more resistant to chemotherapy drugs 4-hydroxycyclophosphamide (left) and vincristine (right), by in vitro drug sensitivity assay. Shown are representative results of three 11B3Δ/Trp53Δframeshift (11B3) or Trp53Δ/Δ (p53) lymphoma cell lines assayed in quadruplicate. *P < 0.05 (Student’s two-tailed t-test). d, e, No functional p53 was detected in various 11B3-deleted tumours as determined by western blotting of p53 and RT–PCR analysis of p21 induction after 4-h ADR treatment. Eμ-Myc;Arf−/− (Trp53+/+) lymphomas were used as a positive control and p21 levels were normalized to untreated cells. Tumours shown in d were identified as missense (tumour 711) or frameshift mutations (tumour 723), while those in e had no detectable mutation. In total eight tumours were analysed. f, The scope of p53 mutations detected in chromosome 11B3-deleted lymphoma cells as determined by sequencing (n = 12). DBD, DNA-binding domain; FS, frameshift mutation; INS, insertion mutation; MS, missense mutation; TAD, transactivation domain; TET, tetramerization domain.

Extended Data Figure 5 Tumours in mice heterozygous for Trp53 mutations lose heterozygosity by duplicating the mutant Trp53 allele.

a, No chromosome 11B3 deletion was detected in various Trp53 heterozygous mutants. Relative allele copy number of various chromosome 11B3 genes, as determined by qPCR analysis of genomic DNA from Eμ-Myc lymphomas derived from germline mice harbouring the following additional alleles: Vav1-cre;Trp53fl/+(exon 2–10 flanked), Trp53+/− (exon 2–6 deleted), Vav1-cre;Trp53LSL-R270H/+ or Vav1-cre;Trp53LSL-R172H/+. Rpa3 on chromosome 6 was used as an endogenous normalization control. b, SNP analysis of tumour or normal tissue (tail) genomic DNA harvested from mice in a, indicating that uniparental disomy occurred during Trp53 LOH, in that C57BL/6 (B6)-derived wild-type Trp53 allele is replaced by 129-derived Trp53 mutant allele. Note that all Trp53-engineered alleles retain 129-derived SNPs; the germline wild-type Trp53 allele is C57BL/6-derived. c, Cartoon summary of the results from a and b.

Extended Data Figure 6 A Trp53 shRNA induces equivalent knockdown in cells with one or two alleles of the Trp53 gene.

Pre-B cells were isolated from Trp53+/+ or Trp53+/− bone marrow, and then transduced with GFP-linked Trp53 shRNA (shp53). GFP+ cells were sorted out by fluorescence-activated cell sorting, and treated with control wild-type pre-B cells in the present of vehicle or 1 μg ml−1 ADR for 4 h. p53 and p21 levels were detected by western blotting and RT–qPCR, respectively. Shown is the representative result of three independent experiments.

Extended Data Figure 7 In the Eμ-Myc model, Trp53 and Eif5a cooperate in tumorigenesis.

Two-colour assay for the cooperation of Trp53 and Eif5a deficiencies on lymphoma genesis. Eμ-Myc HSPCs retrovirally co-transduced with GFP- (shEif5a or shRen) and mCherry-linked shRNAs (shRen, shp53) were transplanted into sublethally-irradiated syngeneic recipients (n = 5 per group). a, b, The resulting tumours were analysed by flow cytometry (a) and the percentage of GFP+mCherry+ lymphoma cells in each configuration was quantified (b). Error bars represent s.d. *P < 0.05, ***P < 0.001 (two tailed t-test).

Extended Data Figure 8 Alox15b deficiency promotes tumorigenesis and increases AA levels.

a, Enrichment fold of shAlox15b.1252 and shAlox15b.2865 in resulting tumours (Fig. 3i, j) compared to those in initiating shRNA libraries. b, Knockdown efficiency of shAlox15b.1252 and shAlox15b.2865 compared to control shRen in NIH3T3 cells, as detected by western blotting and quantitated by ImageJ. c, Relative levels of AA per cell are increased with Alox15b shRNAs as measured by liquid chromatography–mass spectrometry (LC-MS). NIH3T3 cells were transduced with shRen or shAlox15b. n = 3. **P < 0.01 (unpaired two tailed t-test). d, Relative levels of AA per cell in 11B3Δ/Trp53Δframeshift (11B3) lymphoma cells are higher than control cells with Trp53Δ / Δ (p53) as measured by LC-MS. n = 2. P = 0.056 (unpaired two tailed t-test). e, In vitro AA treatments reduce apoptosis, as measured by annexin V staining of pre-B cells after 20 h treatment of indicated concentration of AA. n = 4. *P < 0.05; ***P < 0.001 (unpaired two tailed t-test).

Extended Data Figure 9 11B3 deletion accelerates leukaemogenesis beyond Trp53 loss alone and decreases sensitivity to the BET-protein inhibitor JQ-1.

a, The percentage of 11B3 deletion as determined by qPCR in premalignant c-Kit+ HSPCs (n = 2) and resulting leukaemia cells (tumour; n = 4). **P < 0.01 (unpaired two-tailed t-test). b, Overall survival of recipient mice transplanted with HSPCs from Vav1-cre;11B3fl/Trp53fl or Vav1-cre;Tr53fl/fl co-transduced with both Nf1 and Mll3 shRNAs. **P < 0.01 (log-rank test). c, Complete blood cell counts of recipient mice indicate that there are more total white blood cells (WBCs) and neutrophils, and fewer red blood cells in Vav1-cre;11B3fl/Trp53fl mice compared with the Vav1-cre;Trp53fl/fl control group at 8 weeks post-transplantation. (Note that two mice from each group died before analysis and were not included.) d, Flow cytometry analysis of GFP+mCherry+ leukaemic cells in the bone marrow of moribund mice in a shows that leukaemia cells are myeloid cells in origin and contain both shNf1 and shMll3. e, f, In vitro drug sensitivity of leukaemia cells to araC (e) and the BET-bromodomain inhibitor JQ-1 (f). Shown are representative results of three 11B3Δ/Trp53Δ and two Trp53Δ/Δ leukaemia cell lines assayed in quadruplicate. *P < 0.05 (Student’s two-tailed t-test).

Extended Data Table 1 Number and genotype of progeny resulting from crosses of 11B3fl/+;Ella-cre female mice with Ella-cre male mice

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Liu, Y., Chen, C., Xu, Z. et al. Deletions linked to TP53 loss drive cancer through p53-independent mechanisms. Nature 531, 471–475 (2016). https://doi.org/10.1038/nature17157

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