MYB-QKI rearrangements in angiocentric glioma drive tumorigenicity through a tripartite mechanism


Angiocentric gliomas are pediatric low-grade gliomas (PLGGs) without known recurrent genetic drivers. We performed genomic analysis of new and published data from 249 PLGGs, including 19 angiocentric gliomas. We identified MYB-QKI fusions as a specific and single candidate driver event in angiocentric gliomas. In vitro and in vivo functional studies show that MYB-QKI rearrangements promote tumorigenesis through three mechanisms: MYB activation by truncation, enhancer translocation driving aberrant MYB-QKI expression and hemizygous loss of the tumor suppressor QKI. To our knowledge, this represents the first example of a single driver rearrangement simultaneously transforming cells via three genetic and epigenetic mechanisms in a tumor.

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Figure 1: Recurrent rearrangement involving MYB and QKI in angiocentric gliomas.
Figure 2: Alterations of MYB and QKI occur frequently in human cancers.
Figure 3: MYB-QKI fusion protein functions as a transcription factor, and its molecular effects are observed in angiocentric gliomas.
Figure 4: Angiocentric gliomas exhibit aberrant expression of MYB-QKI due to H3K27ac-associated enhancer translocation and an autoregulatory feedback circuit in which MYB-QKI binds to the MYB promoter.
Figure 5: Human angiocentric gliomas exhibit the translocation of H3K27ac-marked enhancers with an aberrant enhancer associated with the MYB promoter.
Figure 6: MYB-QKI fusion protein and truncated MYB are oncogenic.
Figure 7: MYB-QKI rearrangement disrupts expression of QKI, a tumor-suppressor gene.
Figure 8: MYB-QKI rearrangement contributes to oncogenesis through at least three mechanisms.

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We thank and acknowledge the Dana-Farber Harvard Cancer Center/Pediatric Low-Grade Astrocytoma Consortium and the Children's Brain Tumor Tissue Consortium, including additional participating sites: Ann and Robert Lurie Children's Hospital, Seattle Children's Hospital and Children's Hospital of Pittsburgh for sample contribution, members of the Genomic Platform and Firehose Team at the Broad Institute for assistance with genomic sequencing and analysis, the Neuro-Histology laboratories of Boston Children's Hospital and Brigham and Women's Hospital, H. Homer (Brigham and Women's Hospital) for technical assistance with FISH, and members of the Ligon, Resnick and Beroukhim laboratories for useful discussions.

We acknowledge the following funding sources: A Kids' Brain Tumor Cure Foundation Pediatric Low-Grade Astrocytoma Foundation (P.B., K.L.L., R.B., M.W.K., L.G., C.D.S. and A.C.R.), US National Institutes of Health grant R01NS085336 (A.C.R., A.J.W., P.B.S. and M. Santi), Voices Against Brain Cancer (A.C.R.), the Children's Brain Tumor Foundation (A.C.R. and A.J.W.), the Stop and Shop Pediatric Brain Tumor Program (P.B. and M.W.K.), the Path to Cure Foundation (K.L.L.), US National Institutes of Health grant PO1CA142536 (C.D.S., K.L.L. and R.B.), St. Baldrick's Foundation (P.B.), the American Brain Tumor Association (L.A.R.), the Team Jack Foundation (P.B., M.W.K., R.B. and L.G.), the Andrysiak Fund for LGG (M.W.K.), a Broad Institute Scientific Projects to Accelerate Research and Collaboration (SPARC) grant (A.G.), the Jared Branfman Sunflowers for Life Fund for Pediatric Brain and Spinal Cancer Research (P.B., R.B. and S. Santagata), the Sontag Foundation (K.L.L. and R.B.), the Nuovo-Soldati Foundation (G.B.), the Philippe Foundation (G.B.), Fondation Etoile de Martin (J.G.), the Damon Runyon-Sohn Pediatric Fellowship Award (A.J.W.), a Hyundai Scholar Grant (A.J.W.), the Bear Necessities Pediatric Cancer Foundation (A.J.W. and A.C.R.), the Rally Foundation for Childhood Cancer Research (A.J.W.), National Institute of Neurological Disorders and Stroke (NINDS) grant K08NS087118 (S.H.R.), the Pediatric Brain Tumor Foundation (R.B. and P.B.), Thea's Star of Hope (A.C.R. and A.J.W.), the Hungarian Brain Research Program, grant KTIA_13_NAP-A-V/3, the Janos Bolyai Scholarship of the Hungarian Academy of Sciences (A.K.), NINDS grant 1R01NS091620 (D.A.H.-K.), the Nancy and Stephen Grand Philanthropic Fund (D.A.H.-K.) and the Pediatric Low-Grade Astrocytoma Foundation (D.A.H.-K.).

Finally, we thank and acknowledge the many children and families affected by PLGGs for their generous contributions to this research.

Author information




P.B., L.A.R., P.J., G.B., K.L.L., R.B. and A.C.R. designed research. P.B., L.A.R., P.J., G.B., H.J.H., Y.Z., N.C., A.S., K.B., R.E.H., M. Santi, A.M.B., M. Scagnet, S.M., D.A.H., J.J.P., A.J.W., P.B.S., J.W., R.Z., S.E.S., L.U., R.O'R., W.J.G., K.P., S.H.R., Y.J.K., D.K., B.R.P., A.G.-Y., P.M.H., A.F., H.M., A.A.T., S. Seepo, M.D., P.V.H., D.C.B., S.P., C.H., U.T., A.K., L.B., P.C.B., C.E., F.J.R., D.A.H., D.A.H.-K., S. Santagata, C.D.S., J.E.B., N.J., A.G., J.G., A.H.L., L.G., M.W.K., K.L.L., R.B. and A.C.R. completed the research. P.B., L.A.R., P.J., G.B., J.W., H.J.H., Y.Z., A.J.W., P.B.S., R.Z., A.F., S.E.S., W.J.G., S.H.R., S. Santagata, A.G., J.E.B., A.H.L., A.C.R., K.L.L. and R.B. analyzed the data. J.W., P.V., M.P., D.C.B., C.G., S.P., C.H., U.T., A.K., L.B., P.C.B., C.E., M. Santi, A.M.B., M. Scagnet, S.M., D.A.H., D.A.H.-K., J.J.P., F.J.R., S. Santagata, N.J., A.G., J.G., A.H.L. and L.G. contributed new reagents, algorithms and/or samples. P.B., L.A.R., P.J., G.B., K.L.L., R.B. and A.C.R. wrote the manuscript. K.L.L., R.B. and A.C.R. supervised the study. All authors reviewed, edited and approved the manuscript.

Corresponding authors

Correspondence to Keith L Ligon or Rameen Beroukhim or Adam C Resnick.

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Competing interests

The Dana-Farber Cancer Institute has licensed drug-like derivatives of JQ1 prepared in the Bradner laboratory to Tensha Therapeutics for clinical translation as cancer therapeutics. The Dana-Farber Cancer Institute and J.E.B. have been provided minor equity shares in Tensha Therapeutics.

Integrated supplementary information

Supplementary Figure 1 Significant regions of recurrent copy number alterations in PLGG.

GISTIC q values for amplifications (left) and deletions (right) are plotted across the genome.

Supplementary Figure 2 Driver genomic alterations in PLGGs.

Co-mutation plot of the driver alterations identified in 54 PLGGs profiled with WES and/or array CGH.

Supplementary Figure 3 MYB-QKI binding and transcriptional effects.

(a) Identified MYB-QKI binding peaks at MYB in mNSCs over-expressing MYB-QKI. (b) Expression of MYB, truncated MYB, MYB-QKI and truncated QKI in the cell lines used in mim-1 promoter assays. (c) Linear increases in mim-1 promoter activity with increases in MYB-QKI expression. (d) Enrichment of MYB pathway activation in normal brain, PLGGs without MYB-QKI and angiocentric gliomas with MYB-QKI. Values represent mean expression ± s.e.m.

Supplementary Figure 4 H3K27ac enhancer profiling of the 3′ region of QKI in a human angiocentric glioma.

H3K27ac enhancer peaks are associated with QKI in angiocentric glioma.

Supplementary Figure 5 H3K27ac enhancer formation at MYB in PLGGs.

H3K27ac enhancer formation at the MYB promoter in two human MYB-QKI angiocentric gliomas (top tracks) and a BRAF-altered pilocytic astrocytoma (lower track).

Supplementary Figure 6 Expression of MYB-QKI in HEK293T, NIH3T3 and mNSCs.

(a) MYB promoter activation in HEK293T and NIH3T3 cells with and without expression of MYB-QKI. (b) Exogenous expression of MYB-QKI and truncated MYB in NIH3T3 cells and mNSCs via retroviral transduction. (c) Representative OLIG2 and GFAP immunohistochemical analysis of tumors from mNSCs overexpressing truncated MYB, MYBQKI5 and MYB-QKI as compared to eGFP controls. Positive staining for both OLIG2 and GFAP is observed in a subset of tumor cells in tumors generated from truncated MYB or MYB-QKI5 overexpression, whereas tumors formed by MYB-QKI6 overexpression are negative for OLIG2 and have low levels of GFAP expression. Scale bars, 50 microns.

Supplementary Figure 7 Oncogenic activity of MYB-QKI.

(a) Number of colonies of NIH3T3 cells expressing MYB, MYB-QKI or a vector control in soft agar (left) and representative images (right). NIH3T3 cells overexpressing BRAF-V600E are shown as a positive control. The mean of three replicate measurements is shown. Error bars, s.e.m. (b) Table of tumor penetrance from both NIH3T3 and mNSC models with overall P < 0.001.

Supplementary Figure 8 Suppression of wild-type Qk in mouse neural stem cells expressing MYB-QKI.

(a) Suppression of wild-type Qk in mouse NSCs expressing MYB-QKI following infection with shQKI vectors (or shLacZ control). (b) Proliferation of mNSCs overexpressing eGFP, truncated MYB or MYB-QKI with suppression of wild-type Qk over 5 d in pool 4 (values represent the means of five replicate measurements with s.e.m.). Expression of wild-type Qk relative to shLacZ control is shown. (c) shQk signature defined following suppression of wild-type Qk in mNSCs that overexpress MYB-QKI6.

Supplementary Figure 9 MYB ChIP-seq binding to MYB target genes.

Binding of MYB to MYB target genes in K562 cells using the Abcam 45150 antibody.

Supplementary Figure 10 Validation of MYB ChIP-seq data.

(a) Top four enriched DNA-binding motifs in MYB ChIP-seq peaks obtained from mNSCs overexpressing MYB-QKI. (b) MYB DNA-binding motifs. (c) Venn diagrams showing overlap of the MYB-QKI peaks identified (P-value threshold = 1 × 10–6) as compared to those reported in Zhao et al. and Quintana et al. The P values shown were calculated by χ2 test with Yates correction. Of 2,879 genes identified in our set, 20% (Zhao) and 42% (Quintana) were also identified in the other studies.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–10 and Supplementary Note. (PDF 1378 kb)

Supplementary Table 1

PLGGs included in analysis, including tumor demographics, method of profiling and driver alterations identified (XLSX 28 kb)

Supplementary Table 2

GISTIC amplification peaks (TXT 4 kb)

Supplementary Table 3

GISTIC deletion peaks (TXT 1 kb)

Supplementary Table 4

Differentially expressed genes in neural stem cells expressing eGFP, MYBtr or MYB-QKI (XLSX 6262 kb)

Supplementary Table 5

Gene-Set Enrichment Analysis in neural stem cells expressing eGFP, MYBtr or MYB-QKI (XLS 344 kb)

Supplementary Table 6

Differentially expressed genes in neural stem cells expressing MYB-QKI with shLacZ or shQk (XLSX 3420 kb)

Supplementary Table 7

miRNAs that are differentially expressed in mNSCs expressing MYB-QKI following suppression of wild type Qk (XLSX 37 kb)

Supplementary Table 8

MYB promoter sequence and shQk clones used in experiments (XLSX 21 kb)

Supplementary Table 9

PCR primers used in experiments (XLSX 41 kb)

Supplementary Table 10

ChIP-seq peaks (P = 1.0 × 10-6) identified following MYB ChIPseq in mNSC over-expressing MYBQKI5. Peaks that contain a MYB binding motif (fragment size used in analysis = 200 bp) are shown in the columns labeled MYBL1 or MYB (XLS 2137 kb)

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Bandopadhayay, P., Ramkissoon, L., Jain, P. et al. MYB-QKI rearrangements in angiocentric glioma drive tumorigenicity through a tripartite mechanism. Nat Genet 48, 273–282 (2016).

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