Cell competition is a tumour suppressor mechanism in the thymus

Abstract

Cell competition is an emerging principle underlying selection for cellular fitness during development and disease. Competition may be relevant for cancer, but an experimental link between defects in competition and tumorigenesis is elusive. In the thymus, T lymphocytes develop from precursors that are constantly replaced by bone-marrow-derived progenitors. Here we show that in mice this turnover is regulated by natural cell competition between ‘young’ bone-marrow-derived and ‘old’ thymus-resident progenitors that, although genetically identical, execute differential gene expression programs. Disruption of cell competition leads to progenitor self-renewal, upregulation of Hmga1, transformation, and T-cell acute lymphoblastic leukaemia (T-ALL) resembling the human disease in pathology, genomic lesions, leukaemia-associated transcripts, and activating mutations in Notch1. Hence, cell competition is a tumour suppressor mechanism in the thymus. Failure to select fit progenitors through cell competition may explain leukaemia in X-linked severe combined immune deficiency patients who showed thymus-autonomous T-cell development after therapy with gene-corrected autologous progenitors.

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Figure 1: Progenitor deprivation causes T-ALL.
Figure 2: T-ALL emergence and its prevention by bone marrow reconstitution.
Figure 3: Molecular characterization of T-ALL.
Figure 4: Origin of T-ALL, self-renewal in the thymus, and transcriptome analyses during disease progression.
Figure 5: Cell competition regulates thymocyte turnover.

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Gene Expression Omnibus

Data deposits

Microarray data analysed and reported here have been deposited in the NCBI Gene Expression Omnibus40 and are accessible through GEO accession number GSE56419.

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Acknowledgements

We thank A. Tietz and T. Arnsperger for technical assistance, T. Ashworth and J. Aster, M. Nussenzweig and P. Fink for materials and mice, the animal facilities for mouse husbandry, S. Henze, O. Heil and E. Korpelainen for expression array experiments and support on Chipster. We thank B. Edgar, L. Johnston, T. Boehm, A. Rudensky, R. Medzhitov, M. Muckenthaler, A. Kulodzik, T. Sanda, T. Look, P. Lichter, T. Feyerabend and I. Rode for help and discussions. H.-R.R. was supported by ERC Advanced Grant No. 233074, DFG-SFB 938-project L, and the Helmholtz PCCC Alliance.

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V.C.M. designed and performed experiments, and wrote the paper; K.B., C.B. and C.L. performed experiments; V.C.M., D.J., S.E.M., B.B. and T.H. performed bioinformatic analyses; V.R. obtained the magnetic resonance imaging images; F.L. evaluated the pathological findings; H.J.F. provided essential support and edited the paper; and H.-R.R. conceived and supervised the study, and wrote the paper.

Corresponding author

Correspondence to Hans-Reimer Rodewald.

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The authors declare no competing financial interests.

Extended data figures and tables

Extended Data Figure 1 Characterization of T-ALL.

a, Splenocytes from Rag2−/−γc−/−KitW/Wv recipient mice with T-ALL were gated for CD45.1+ thymus donor cells, and analysed for CD4 and CD8 expression. All T-ALL samples were analysed in this manner. b, RAG2p-GFP reporter thymus-grafted (top), and non-transplanted (bottom) kidneys of a T-ALL+ recipient. Bright field and fluorescent images superimposed in the top panel (scale bars, 5 mm). All T-ALL+ mice had thymic tumours, and all RAG2p-GFP reporter thymus-derived T-ALL expressed Rag2 based on in situ fluorescence (shown here), or based on flow cytometry (Extended Data Fig. 5). c, Volume of spleens by magnetic resonance imaging (MRI). d, Spleen cellularity. e, Ki67 expression in CD4+ and CD8+ control splenocytes (left panel), and in T-ALL samples; each colour is an individual tumour (right panel). Control splenocytes or T-ALL cells unstained for Ki67 are shown in the grey shaded curves. f, Immunostaining of spleen cryosections of the indicated mice (n = 2 for T-ALL, and n = 1 for the controls) stained for T cells (CD4 plus CD8 in red), B cells (B220 in green), and erythrocytes (Ter119 in blue). Scale bar, 200 μm. g, Liver cryosections of the indicated samples (n = 4 for T-ALL, and n = 1 for the control) were stained with haematoxylin and eosin. Mice with T-ALL had perivascular and periportal infiltrates of a monomorphous small neoplasm that infiltrated into the adjacent liver parenchyma. At higher magnification (not shown), the neoplastic cells appeared medium-sized to large and showed a pronounced nuclear pleomorphism indicated by irregular edged nuclear contours with coarsely plumped chromatin. Cell borders were distinct, and a cytoplasmic rim was nearly invisible. These histomorphological findings were consistent with liver infiltration of a malignant haematopoietic neoplasm. Scale bar, 400 μm. h, Liver cryosections of the indicated samples (n = 2 for T-ALL, and n = 1 for the control) were immunostained for CD8 (red) and counter-stained for DAPI (blue). Scale bars, 50 μm. i, MRI analysis of T-ALL. Splenocytes from T-ALL+ mice were injected intravenously into athymic nude (Foxn1nu/nu) mice. T-ALL+ nude mice were killed and immediately scanned by MRI (n = 10). Images shown are from a representative T-ALL+ mouse in two levels, revealing enlarged kidneys, liver, spleen and lymph nodes reflecting T-ALL dissemination (upper panels). Images from a nude mouse not receiving leukaemic cells (n = 2) are shown as controls (lower panels).

Extended Data Figure 2 Transplantation of T-ALL into nude (Foxn1nu/nu) mice.

a, Analyses of CD4 and CD8 expression (top row), and CD8 and the RAG2p-GFP reporter (bottom row) in the spleens of a normal B6/Ly5.1 mouse (left), an unmanipulated nude mouse (middle), and a nude mouse 3 weeks after receiving 105 splenocytes from a T-ALL+ Rag2−/−γc−/−KitW/Wv recipient (right). Data are representative for recipients listed in b. b, Summary of T-ALL sample numbers (primary (1°) T-ALL), numbers of cells transferred per nude mouse (cells transferred), numbers of nude mice injected per T-ALL sample (secondary (2°) recipients), numbers of nude mice developing T-ALL (T-ALL positive), and time in days until onset of the disease, or end of observation period (time).

Extended Data Figure 3 TCR-β rearrangements in T-ALL.

a, PCR analyses of to Jβ1 (top), and to Jβ2 (bottom) rearrangements on genomic DNA from T-ALL+ spleen samples. TCR-β rearrangements were identified by PCR using a pool of -gene-specific forward primers and reverse primers to either Jβ1.7 (top) or Jβ2.7 (bottom). Dominant, T-ALL-derived TCR-β rearrangements were visualized by gel electrophoresis, and PCR products were cloned for DNA sequencing. b, T-ALL samples analysed (sample ID), identified and elements ( − ), and classification of in-frame, or out-of-frame rearrangements based on the reading frames of the obtained sequences (productive/non-productive).

Extended Data Figure 4 Experiments addressing prevention of T-ALL by reconstitution with functional wild-type bone marrow.

a, Experimental design: Rag2−/−γc−/−KitW/Wv mice were transplanted with wild-type thymus (as described in Fig. 1a), and at 1, 6 or 10 weeks after thymus grafting were injected intravenously with 3 × 105 lineage-negative wild-type bone marrow cells (BM). T-ALL was prevented in mice receiving bone marrow 1 week after thymus transplantation (n shown in Fig. 2b). b, Flow cytometric analysis of bone marrow stem/progenitors demonstrating engraftment of donor ‘rescue’ bone marrow (left panels), and the cellular phenotypes in the thymus grafts (middle and right panels) (n shown in Fig. 2b). Bone marrow cells are pre-gated as lineage marker-negative (lin) and donor cells (CD45.1+). Thymocytes are pre-gated for cells of graft origin (CD45.2+ CD45.1+, middle panels), and cells of bone marrow ‘rescue’ origin (CD45.1+, right). Numbers in the plots refer to the percentage of gated cells. For each condition (bone marrow reconstitution at 6 or 10 weeks post thymus transplantation), examples are shown for ongoing T-cell development from the wild-type bone marrow, but not the thymus-resident cells, with no evidence for T-ALL (first and third rows), and for cases in which T-ALL developed while T-cell development of wild-type bone marrow origin did not prevail (second and fourth rows). The bone marrow data indicate that prevention of T-ALL was associated with stronger HSC engraftment by wild-type donor cells, however, it cannot be excluded that the overt T-ALL already suppressed haematopoiesis in the bone marrow, and hence the difference in the bone marrow may be secondary to the emergence of T-ALL.

Extended Data Figure 5 T-ALL emergence.

a, Peripheral blood cells (gated for CD45.1+) from a normal control mouse (B6/Ly5.1), and a Rag2−/−γc−/−KitW/Wv recipient carrying a RAG2p-GFP (CD45.1+) donor thymus were analysed by flow cytometry at the indicated time points. GFP-positive cells are shown in green. b, The recipient shown in a was killed on week 18, and the indicated organs were analysed. RAG2p-GFP+-gated cells are green. Data are representative for RAG2p-GFP+ thymus-derived T-ALL (n = 12).

Extended Data Figure 6 Mutations in and aberrant expression of Notch1 in T-ALL.

a, Exons 26, 27 and 34 of Notch1 were sequenced and the mutation position, mutation type and predicted consequence for the protein are listed for all analysed T-ALL. All individual mutations were heterozygous and correspond to the triangles depicted in Fig. 3e. Substitutions (sub), insertions (ins), duplications (dup), complex deletions and insertions (indel), predicted frameshift (fr) and early STOP codons (eSTOP) are indicated, as well as the protein domains predicted to be affected: amino or carboxyl heterodimerization domains (HD-N or HD-C, respectively), transactivation domain (TAD), and PEST domain. b, Schematic view of the Notch1 locus, depicting 5′ deletions (ΔNotch1), and positions of the annealing sites for the primers used to detect deletions (red triangles). Exons are indicated by black bars. Genomic DNA from Rag+/+ (n = 25) and Rag−/− (n = 5) T-ALL was analysed by PCR for the presence of the deletion29. Amplification of the band with 500 bp (ΔNotch1; upper gel) identifies the deletion. The non-deleted locus is too large to yield a band; hence, absence of the band indicates no deletions. Glycoprotein 130 (gp130) was amplified as positive control for the presence of the DNA template. Deletions were seen in 13/25 Rag1+/+, but in 0/5 Rag1−/− T-ALL. c, PCR products were sequenced to characterize the junctions. The germline Notch1 sequence is shown on the top (GL), revealing the sequence homology to the recombination signal sequence (RSS) highlighted in bold. The conserved residues in the putative cryptic RSS in the 5′ region of the Notch1 locus are shown in red. For 10 deletions, the sequences flanking the junctions are shown, with evidence of N nucleotide addition. The positive control DNA was derived from a T-ALL cell line that contained the deletion (provided by Ashworth and Aster). d, cDNAs from spleen (s) and thymus (t) from normal mice, and from T-ALL+ spleens were analysed for expression of canonical Notch1 promoter transcripts (E1E6), alternative Notch1 promoter transcripts (E1aE6), Hes1, and β-actin.

Extended Data Figure 7 Venn diagrams.

Diagrams underlay the transcriptome analysis in Fig. 4. The transcriptomes from normal thymi, thymus grafts (10 weeks after transplantation) and T-ALL samples were analysed by pairwise comparisons: normal thymus versus thymus grafts (top diagram); thymus grafts versus T-ALL (lower right diagram); normal thymus versus T-ALL (lower left diagram). The Venn diagram shows numbers of genes with expression changes of ≥ fourfold for each comparison. The overlapping regions show the genes that were common to the different comparisons. The numbers 60, 22 and 64 (in bold) correspond to the genes displayed in the heat maps d, e, and f, respectively, in Fig. 4.

Extended Data Figure 8 Molecular correlation between progenitor deprivation-driven murine T-ALL and human T-ALL.

a, b, Genes upregulated in murine T-ALL (list from Fig. 4f) were compared to the transcriptome of human T-ALL (a), and human B-ALL (b). Upregulated changes are significantly and positively correlated with the expression of the orthologous genes all human T-ALL subtypes (GSE26713, 117 patient samples) (a). Upregulated changes do not correlate with the expression of the orthologous genes in human B-ALL subtypes (GSE13351) (b). The 73 patient samples in GSE13351 also included 15 T-ALL samples that correlated with the mouse T-ALL samples (bottom row). c, Intensity values for the indicated genes were obtained from the normalized transcriptome data. Mean and standard deviation are displayed.

Extended Data Figure 9 Sensitivity and stage of competition between wild-type and IL-7-unresponsive (γc−/−) T-cell progenitors.

a, A total of 3 × 105 lin donor bone marrow cells were either pure (100%) wild-type (γc+/+) (CD45.1+; black bars) cells, or pure (100%) γc−/− (CD45.2+; red bars) cells, or mixtures of both genotypes (ratios indicated at the top), and used to reconstitute 1,100 rad-irradiated recipients (CD45.1+CD45.2+). Each bar corresponds to a single mouse (no. 1–18). Percentages of chimaerism within bone marrow linSca-1+Kit+ (LSK) (that contain haematopoietic stem and early progenitor cells) (top), within thymic TN2 (middle), and TN3 (bottom) are displayed. Mice were analysed 4 weeks after bone marrow reconstitution. In the recipient bone marrow, the ratio of γc+/+ versus γc−/− HSC donor engraftment closely mirrored the proportions of the input chimaerism. At the TN2 stage, few γc−/− T-cell progenitors were still detectable, but by the TN3 stage they were completely outcompeted by wild-type donor, or residual host progenitors. b, Cell numbers of TN2 (top) and TN3 (bottom) of wild type (left panels, black bars) or γc−/− (right panels, red bars) are displayed as averaged cell counts for each group of mice shown in a. Note that the scales of the y axis differ between the left and right panels.

Extended Data Figure 10 Comparison of young versus old progenitors in the presence, or absence of competition: transcriptome, Bcl2 mRNA and protein expression, and apoptosis.

a, Venn diagram representing the overlap between pairwise comparisons of gene expression (threshold ≥ twofold) between young and old with competition (green circle), and between young and old without competition (orange circle). To correct for potential developmental differences in gene expression at the TN2 to TN3 transition, we sorted TN2 and TN3 cells from a normal thymus. The numbers 9, 26 (in Fig. 5 only 17/26 genes are displayed), and 19 (all in bold) correspond to the genes displayed in the heat maps in Fig. 5j, k and l, respectively. b, Bcl2 mRNA levels as determined by fluorescence intensity in the expression array from sorted young and old TN2/TN3 cells. c, Bcl2 protein levels, measured by intracellular FACS staining after gating on young and old TN3 cells, are depicted as mean fluorescence intensity (MFI). d, Percentage of annexin+ cells in TN3.

Supplementary information

Supplementary Information

This file contains contains Supplementary Discussion, Supplementary References, and Supplementary Tables 1–5. Supplementary Tables 1 and 2 refer to genomic gains and losses detected in T-ALL by array comparative genomic hybridization (aCGH), considered cancer-related according to the Ingenuity Pathway Analysis. Supplementary Tables 3–5 refer to ≥2 fold-change differences in transcriptome analyses between normal thymus versus thymus grafts (Table 3), between thymus grafts versus T-ALL (Table 4), and between normal thymus versus T-ALL (Table 5). Genes displayed were considered to be cancer-related according to Ingenuity Pathway Analysis. (PDF 325 kb)

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Martins, V., Busch, K., Juraeva, D. et al. Cell competition is a tumour suppressor mechanism in the thymus. Nature 509, 465–470 (2014). https://doi.org/10.1038/nature13317

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