Abstract
Loss-of-function mutations of cyclic-AMP response element binding protein, binding protein (CREBBP) are prevalent in lymphoid malignancies. However, the tumour suppressor functions of CREBBP remain unclear. We demonstrate that loss of Crebbp in murine haematopoietic stem and progenitor cells (HSPCs) leads to increased development of B-cell lymphomas. This is preceded by accumulation of hyperproliferative lymphoid progenitors with a defective DNA damage response (DDR) due to a failure to acetylate p53. We identify a premalignant lymphoma stem cell population with decreased H3K27ac, which undergoes transcriptional and genetic evolution due to the altered DDR, resulting in lymphomagenesis. Importantly, when Crebbp is lost later in lymphopoiesis, cellular abnormalities are lost and tumour generation is attenuated. We also document that CREBBP mutations may occur in HSPCs from patients with CREBBP-mutated lymphoma. These data suggest that earlier loss of Crebbp is advantageous for lymphoid transformation and inform the cellular origins and subsequent evolution of lymphoid malignancies.
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Acknowledgements
The Huntly laboratory is funded by the ERC (grant 647685 COMAL), KKLF, MRC, Bloodwise, the Wellcome Trust (WT) and the Cambridge NIHR BRC. We acknowledge the WT/MRC centre grant (097922/Z/11/Z) and support from WT strategic award 100140. D.S. is a Postdoctoral Fellow of the Mildred-Scheel Organisation, German Cancer Aid. We thank C. Cossetti, M. Maj and R. Schulte at the CIMR Flow Cytometry Core for their help with cell sorting. This research was supported by the Cambridge NIHR BRC Cell Phenotyping Hub. E.L. is funded by a Sir Henry Dale fellowship from the WT/Royal Society.
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S.J.H. designed and performed experiments, analysed data and wrote the paper. G.G. performed FACS, serial replating and transplantation experiments. H.Y. performed ChIP-Seq and qRT-PCR. S.V. performed bioinformatics analyses. O.S. maintained the mouse lines and performed experiments. R.B.-R. performed BCR amplification, sequencing and analysis. M.R. performed exome sequencing and bioinformatics analyses. A.C. designed and performed the allele-specific PCR. D.S. performed western blotting. L.Y. performed flow cytometry. W.-I.C., H.O., F.B., P.G., A.E., S.F. and T.S. provided technical assistance. N.B. and P.M. provided the CD19-Cre mice. A.S. optimized immunofluorescence experiments. W.Z. performed immunohistochemistry. A.P.H. and E.L. helped with design and sorting of HSPCs from patients. J.O. and J.F. provided patient samples. D.H. and K.G.S. designed experiments; P.W. analysed histology and immunohistochemistry. A.C. and M.Q.D. designed and analysed allele-specific PCR. D.J.A. analysed exome sequencing data. B.J.P.H. designed and analysed experiments and wrote the paper.
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Integrated supplementary information
Supplementary Figure 1 Additional information for lymphoid phenotype and characterization of the IL7Rα + population in Mx-Crebbp−/− mice.
(a) Representative flow plots gated on Lin− IL7Ra+ cells demonstrating a decreased CLP compartment in Mx1-Crebbp−/− compared to WT mice. (b) However, when assessed compared to all live cells, no significant alterations in the CLP population or downstream B cell compartments were detected between genotypes (by 2-sided t-test). (c) At the early time point of assessment (8–10 weeks post pIpC), both B- and T-cells are non-significantly decreased in Mx-Crebbp−/− mice (by 2-sided t-test). (d) No significant differences in the frequency (left panel) or cell number (right panel) of early and late B cell subsets in the blood of Mx-Crebbp−/− and WT mice (by 2-sided t-test). All box plots in panels b–d represent the median with interquartile range and whiskers show the minimum and maximum values, n = 6 mice per genotype; 3 mice per genotype were quantified in 2 independent experiments. (e) The IL7-Rα + population demonstrates both lymphoid (left panel) and to a lesser extent myeloid potential (right panel), however genotype specific differences between Mx-Crebbp−/− and WT mice in terms of proliferation and self-renewal are only seen under lymphoid conditions. Box plots show the median with interquartile range and whiskers show the minimum and maximum values. For lymphoid assays, n = 6 mice per genotype; 2 mice per genotype quantified in 3 independent experiments (round 1 ∗∗∗p = 0.0002 and round 3 ∗p = 0.0181, all by 2-sided t-test). For myeloid assays, n = 4 mice per genotype; 2 mice per genotype quantified in 2 independent experiments. Photomicrograph inserts in left panel show that Crebbp−/− IL7Ra+ cells produce larger colonies per plating (representative 3rd round colonies per genotype, scale bar 50 μM) in lymphoid conditions. (f) Further GSEA of the differentially expressed dataset between Mx-Crebbp−/− and WT IL7-Rα+ progenitors demonstrates enrichment for ES core, HSC and proliferative phenotypes.
Supplementary Figure 2 Gating strategy for pre-malignant cells and next generation sequencing strategy for clonal IgH repertoire analysis.
(a) Example of the gating strategy used for flow cytometry experiments. The specific strategy used to isolate B220 + Mac1 + cells from the spleen of pre-malignant mice in Fig. 3c is shown. (b) Schema of the PCR strategy used to sequence the IgH repertoire in individual mice. Multiple upstream IgH and specific J specific primers (as exemplified by G1 and G2 in the illustrated gel in b) were used to amplify the clonal IgH rearrangements, prior to adapter ligation, NGS library preparation and 300-bp paired-end sequencing on a Mi-Seq analyser. (c) Representative gels showing amplification of peripheral blood and tumour tissue from a number of animals.
Supplementary Figure 3 Transcriptional and epigenetic abnormalities in the evolution of Crebbp−/− Lymphoma.
(a) Western blot demonstrates that, although the levels are variable, both the Crebbp−/− LPD/Lymphomas demonstrate a global decrease in H3K27Ac by comparison with the WT lymphomas. Unprocessed scans of blots are shown in Supplementary Fig. 8. (b) IGV screenshot for the Ebf1 locus, which demonstrates the downregulation of gene expression in the Crebbp−/− LPD in comparison to WT-B-cells, as well as the loss of H3K27Ac at two intragenic enhancer regions (boxed) that demonstrate Crebbp binding in normal B-cells.
Supplementary Figure 4 Genomic landscape and mutational pattern of Crebbp−/− LPD/Lymphoma.
(a) Predicted mutations in the top most recurrently altered genes and three genes known to be mutated in human lymphomas (Gna13, Card11 and Hist1h1d) are shown across our cohort of 27 samples. The samples are lymphomas/LPD unless otherwise stated (PM = premalignant B220+/Mac1Int cells, LSK = lin− Sca1+ cKit+ HSPC) and are all Crebbp−/− unless designated WT. (b) Western blotting demonstrates phosphorylation of Erk1/2 in both WT and Crebbp−/− lymphomas and phosphorylation of Stat3 in Crebbp−/− LPD 2. No activation of these pathways are demonstrated in normal WT B-cells (WT B220 + cells). Unprocessed scans of blots are shown in Supplementary Fig. 8. Comparisons of the pattern of mutations identified in Crebbp−/− deficient tumours by exome sequencing with human signatures of mutation by (c)—hierarchical clustering and (d)—Cosine correlation coefficient analysis. Both analyses demonstrate the highest correlation with Signature 1 (highlighted in red boxes). Signature 1 is associated with ageing.
Supplementary Figure 5 Epigenetic priming upon Crebbp loss.
(a) Table showing the number of genes up and downregulated along the continuum of lymphoma evolution in Mx-Crebbp−/− mice, along with downregulated differential H3K27Ac peaks at the two timepoints tested (the IL7-Rα + progenitors and the Crebbp−/− LPD), and the overlap with downregulated genes as a correlation of the epigenetic and transcriptional abnormalities. These demonstrate the sequential increase in differential gene expression and suggest that epigenetic changes precede gene expression changes. (b) Longitudinal comparisons of RNA-Seq and H3K27Ac peaks are shown for IL7-Rα + progenitors from Mx-Crebbp−/− and WT mice and for Crebbp−/− lymphomas and WT B-cells at the ‘classical’ MHC Class II locus. At the early time point in the IL7-Rα + progenitors (upper 4 tracings), no differences in expression level by RNA-Seq are seen for any of the genes shown (H2-0b, H2-Ab1, H2-Aa, H2-Eb1, H2-Eb2 or the pseudogene H2-Ea-ps), although significant loss of H3K27Ac is already observed at some loci (boxed in black). At the later timepoint, previous acetylation decreases remain and appear comparatively accentuated (in black again), however novel changes are also seen (boxed in red), including a decreased binding across the whole superenhancer between H2-Aa and H2-Eb1. These epigenetic alterations translate into more wide ranging downregulation of multiple genes in the LPD/lymphomas including H2-Ob, H2-Ab1, H2-Eb2 and H2-Ea-ps. These and other data (Fig. 2 and Supplementary Fig. 3) suggest that early loss of Crebbp generates acetylation changes that immediately alter gene expression at only a few loci. However, early loss of acetylation appears to ‘prime’ certain other loci for gene downregulation at later timepoints. We speculate that the effects of other mutations, acquired at least in part through the DDR defect associated with Crebbp loss, may contribute to this later dysregulation.
Supplementary Figure 6 Further comparisons of CD19-Crebbp−/− and WT mice.
(a) PCR analysis of efficiency of excision of Crebbp in Cd19-Crebbp−/− and Mx-Crebbp−/− mice. (b) Percentage of B-cells in the peripheral blood of Cd19-Crebbp−/− mice versus WT (c) CFC generated from IL7-Rα + progenitors under lymphoid conditions in comparison to WT mice. (d) Proportion of CLP in BM (left panel) and pro-B cells in the spleen between Cd19-Crebbp−/− and WT mice (∗p = 0.036 by 2-sided t-test, Supplementary Table 26). (e) Frequency (left panel) and cell number (right panel) of early and late B cell subsets in the blood of Cd19-Crebbp−/− and WT mice. All box-plots in panels b–e show the median and interquartile range and whiskers represent maximum and minimum values, n = 6 mice per genotype; 3 mice per genotype quantified in 2 independent experiments. (f) Aberrant B220+/MacInt populations are detected in Cd19-Crebbp−/− (47 mice) at an increased frequency over WT (41 mice).
Supplementary Figure 7 Allele specific (AS) PCR strategy and confirmation.
(a) Schematic displays the two PCR assays employed to detect the CCT genomic deletion in patient number 2 that leads to the S1608delS mutation. The forward and reverse AS primers are shown with the size of the predicted forward and reverse amplicons. (b) Analytical sensitivity of AS-PCR. Serial dilutions of the tumour DNA sample (Mut) containing the c.5039_5042delCCT mutation are shown using the upstream AS-PCR assay (left panel) and downstream AS-PCR assay (right panel). −ve—Negative control, WT—wild-type. (c) Downstream AS-PCR confirming reproducible amplification of a 209 bp product in the CD34 + CD38 + progenitor population grown under myeloid conditions. (d) Confirmation of the presence of the CCT deletion (boxed) in the AS-PCR products generated from both the upstream and downstream assays by Sanger sequencing.
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Horton, S., Giotopoulos, G., Yun, H. et al. Early loss of Crebbp confers malignant stem cell properties on lymphoid progenitors. Nat Cell Biol 19, 1093–1104 (2017). https://doi.org/10.1038/ncb3597
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DOI: https://doi.org/10.1038/ncb3597
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