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The landscape of somatic mutations in infant MLL-rearranged acute lymphoblastic leukemias

Abstract

Infant acute lymphoblastic leukemia (ALL) with MLL rearrangements (MLL-R) represents a distinct leukemia with a poor prognosis. To define its mutational landscape, we performed whole-genome, exome, RNA and targeted DNA sequencing on 65 infants (47 MLL-R and 18 non–MLL-R cases) and 20 older children (MLL-R cases) with leukemia. Our data show that infant MLL-R ALL has one of the lowest frequencies of somatic mutations of any sequenced cancer, with the predominant leukemic clone carrying a mean of 1.3 non-silent mutations. Despite this paucity of mutations, we detected activating mutations in kinase-PI3K-RAS signaling pathway components in 47% of cases. Surprisingly, these mutations were often subclonal and were frequently lost at relapse. In contrast to infant cases, MLL-R leukemia in older children had more somatic mutations (mean of 6.5 mutations/case versus 1.3 mutations/case, P = 7.15 × 10−5) and had frequent mutations (45%) in epigenetic regulators, a category of genes that, with the exception of MLL, was rarely mutated in infant MLL-R ALL.

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Figure 1: Somatic mutations detected by whole-genome sequencing of infant MLL-R ALL.
Figure 2: Recurrently mutated genes detected in 47 cases of infant MLL-R ALL.
Figure 3: Clonal evolution from diagnosis to relapse in infant INF002.
Figure 4: Mutational profiles of infant and non-infant MLL-R leukemia.

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Acknowledgements

We thank all the patients and their parents from the St. Jude Children's Research Hospital (USA), the Department of Pediatrics at Lund University Hospital (Sweden) and the children's hospitals associated with the Australian and New Zealand Children's Haematology and Oncology Group. We thank B. Pappas and S. Malone for IT infrastructure. We thank the Tissue Resources Laboratory, the Flow Cytometry and Cell Sorting Core and the Clinical Applications of Core Technology Laboratories of the Hartwell Center for Bioinformatics and Biotechnology of St. Jude Children's Research Hospital. We thank E. Parganas and J. Ihle (St. Jude Children's Research Hospital) for the mouse BaF3 cells. This work was funded by the St. Jude Children's Research Hospital–Washington University Pediatric Cancer Genome Project and the American Lebanese and Syrian Associated Charities of St. Jude Children's Research Hospital and was supported by a grant from the US National Institutes of Health (P30 CA021765). A.K.A. was supported by the Swedish Childhood Cancer Society, the Swedish Research Council, the Swedish Cancer Society, BioCARE and the Gunnar Nilsson Cancer Foundation. C.G.M. is a Pew Scholar in Biomedical Sciences and a St. Baldrick's Scholar.

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Contributions

A.K.A., J.R.D., T.A.G., J.Z., J. Ma and R.K.W. designed all experiments. J.Z. and J. Ma led the sequencing analysis. J.Z., J. Ma, J.W., X.C., M.P., M.R., G.W., Y.L., J.B., P.G., M.E., P.N., L.W., C.L., L.D. and E.R.M. performed the computational data analyses. G.S. provided bioinformatics support. A.K.A., L.H. and C.G.M. analyzed SNP array data. R.H. and R.K. performed structural modeling. A.L.G. and J.D. performed functional work on the FLT3 and PI3K pathway mutations. J.N., J.E., M.P., B.V. and D.Y. performed validation experiments. K.B. performed RNA-seq. J.E. and J. Manne performed exome sequencing. C.G.M., H.M. and D.P.-T. prepared samples. S.P., G.K., L.S., C.C. and D.P. performed statistical analysis. R.S., N.C.V., A.C., A.R., D.C., J.H., T.F. and C.-H.P. provided annotated patient samples. S.R. and S.S. provided molecular genetics, cytogenetics and FISH data. J. Ma and T.A.G. preformed critical reading and contributed to the writing of the manuscript. A.K.A. and J.R.D. wrote the manuscript.

Corresponding authors

Correspondence to Anna K Andersson, Tanja A Gruber or James R Downing.

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The authors declare no competing financial interests.

Additional information

A list of contributing authors appears in the Supplementary Note.

Supplementary information

Supplementary Text and Figures

Supplementary Note, Supplementary Tables 1–5, 8–10, 12, 13, 15, 16, 18–22, 24–34, and 37–41, and Supplementary Figures 1–48. (PDF 9872 kb)

Supplementary Table 6

Validated tier 1 sequence mutations for the 22 infant discovery cases. (XLSX 41 kb)

Supplementary Table 7

Validated structural variants for the 22 infant discovery cases. (XLSX 28 kb)

Supplementary Table 11

Mutant allele expression as determined by RNA sequencing. (XLSX 43 kb)

Supplementary Table 14

Concordance of CNAs identified by WGS and SNP array for the discovery cohort. (XLSX 44 kb)

Supplementary Table 17

RNA sequencing identifies novel fusion genes. (XLSX 57 kb)

Supplementary Table 23

Sequence mutations identified by targeted resequencing of 232 genes in the validation cohort. (XLSX 20 kb)

Supplementary Table 35

Mutation summary of all samples analyzed as part of this study. (XLSX 23 kb)

Supplementary Table 36

Validated sequence mutations in non-infant MLL-R leukemia. (XLSX 56 kb)

Supplementary Table 42

The 633 epigenetic regulatory genes investigated. (XLSX 20 kb)

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Andersson, A., Ma, J., Wang, J. et al. The landscape of somatic mutations in infant MLL-rearranged acute lymphoblastic leukemias. Nat Genet 47, 330–337 (2015). https://doi.org/10.1038/ng.3230

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