Developmental origins and emerging therapeutic opportunities for childhood cancer

Abstract

Cancer is the leading disease-related cause of death in children in developed countries. Arising in the context of actively growing tissues, childhood cancers are fundamentally diseases of dysregulated development. Childhood cancers exhibit a lower overall mutational burden than adult cancers, and recent sequencing studies have revealed that the genomic events central to childhood oncogenesis include mutations resulting in broad epigenetic changes or translocations that result in fusion oncoproteins. Here, we will review the developmental origins of childhood cancers, epigenetic dysregulation in tissue stem/precursor cells in numerous examples of childhood cancer oncogenesis and emerging therapeutic opportunities aimed at both cell-intrinsic and microenvironmental targets together with new insights into the mechanisms underlying long-term sequelae of childhood cancer therapy.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Epigenetic dysregulation and therapeutic opportunities in midline gliomas with histone mutations.
Fig. 2: Developmental origins of childhood cancer.
Fig. 3: Microglial inflammation is central to childhood cancer-therapy-related cognitive impairment.

References

  1. 1.

    Siegel, R. L., Miller, K. D. & Jemal, A. Cancer statistics, 2018. CA Cancer J. Clin. 68, 7–30 (2018).

    Article  PubMed  Google Scholar 

  2. 2.

    Gröbner, S. N. et al. The landscape of genomic alterations across childhood cancers. Nature 555, 321–327 (2018).

    PubMed  Article  CAS  Google Scholar 

  3. 3.

    Ma, X. et al. Pan-cancer genome and transcriptome analyses of 1,699 paediatric leukaemias and solid tumours. Nature 555, 371–376 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  4. 4.

    Funato, K., Major, T., Lewis, P. W., Allis, C. D. & Tabar, V. Use of human embryonic stem cells to model pediatric gliomas with H3.3K27M histone mutation. Science 346, 1529–1533 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  5. 5.

    Pathania, M. et al. H3.3K27M Cooperates with Trp53 Loss and PDGFRA Gain in Mouse Embryonic Neural Progenitor Cells to Induce Invasive High-Grade Gliomas. Cancer Cell. 32, 684–700 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  6. 6.

    Li, Z. et al. Developmental stage-selective effect of somatically mutated leukemogenic transcription factor GATA1. Nat. Genet. 37, 613–619 (2005).

    CAS  PubMed  Article  Google Scholar 

  7. 7.

    Huntly, B. J. et al. MOZ-TIF2, but not BCR-ABL, confers properties of leukemic stem cells to committed murine hematopoietic progenitors. Cancer Cell. 6, 587–596 (2004).

    CAS  PubMed  Article  Google Scholar 

  8. 8.

    Cozzio, A. et al. Similar MLL-associated leukemias arising from self-renewing stem cells and short-lived myeloid progenitors. Genes Dev. 17, 3029–3035 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  9. 9.

    Ng, J. M. et al. Generation of a mouse model of atypical teratoid/rhabdoid tumor of the central nervous system through combined deletion of Snf5 and p53. Cancer Res. 75, 4629–4639 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  10. 10.

    Han, Z. Y. et al. The occurrence of intracranial rhabdoid tumours in mice depends on temporal control of Smarcb1 inactivation. Nat. Commun. 7, 10421 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  11. 11.

    Vitte, J., Gao, F., Coppola, G., Judkins, A. R. & Giovannini, M. Timing of Smarcb1 and Nf2 inactivation determines schwannoma versus rhabdoid tumor development. Nat. Commun. 8, 300 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  12. 12.

    Wu, G. et al. The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma. Nat. Genet. 46, 444–450 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  13. 13.

    Lannon, C. L. & Sorensen, P. H. ETV6-NTRK3: a chimeric protein tyrosine kinase with transformation activity in multiple cell lineages. Semin. Cancer Biol. 15, 215–223 (2005).

    CAS  PubMed  Article  Google Scholar 

  14. 14.

    Wu, G. et al. Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas. Nat. Genet. 44, 251–253 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  15. 15.

    Schwartzentruber, J. et al. Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature 482, 226–231 (2012).

    CAS  PubMed  Article  Google Scholar 

  16. 16.

    Khuong-Quang, D. A. et al. K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas. Acta Neuropathol. 124, 439–447 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  17. 17.

    Louis, D. N. et al. The2016 world health organization classification of tumors of the central nervous system: a summary. Acta Neuropathol. 131, 803–820 (2016).

    PubMed  Article  Google Scholar 

  18. 18.

    Lewis, P. W. et al. Inhibition of PRC2 activity by a gain-of-function H3 mutation found in pediatric glioblastoma. Science 340, 857–861 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  19. 19.

    Bender, S. et al. Reduced H3K27me3 and DNA hypomethylation are major drivers of gene expression in K27M mutant pediatric high-grade gliomas. Cancer Cell. 24, 660–672 (2013).

    CAS  PubMed  Article  Google Scholar 

  20. 20.

    Filbin, M. G. et al. Developmental and oncogenic programs in H3K27M gliomas dissected by single-cell RNA-seq. Science 360, 331–335 (2018).

    CAS  PubMed  Article  Google Scholar 

  21. 21.

    Monje, M. et al. Hedgehog-responsive candidate cell of origin for diffuse intrinsic pontine glioma. Proc. NatlAcad. Sci. USA 108, 4453–4458 (2011).

    CAS  Article  Google Scholar 

  22. 22.

    Larson, J. D. et al. Histone H3.3 K27M accelerates spontaneous brainstem glioma and drives restricted changes in bivalent gene expression. Cancer Cell. 35, 140–155.e7 (2019).

    PubMed  Article  CAS  Google Scholar 

  23. 23.

    Lehnertz, B. et al. H3 K27M/I mutations promote context-dependent transformation in acute myeloid leukemia with RUNX1 alterations. Blood 130, 2204–2214 (2017).

    CAS  PubMed  Article  Google Scholar 

  24. 24.

    Pajtler, K. W. et al. Molecular heterogeneity and CXorf67 alterations in posterior fossa group A (PFA) ependymomas. Acta Neuropathol. 136, 211–226 (2018).

    CAS  PubMed  Article  Google Scholar 

  25. 25.

    Dubuc, A. M. et al. Aberrant patterns of H3K4 and H3K27 histone lysine methylation occur across subgroups in medulloblastoma. Acta Neuropathol. 125, 373–384 (2013).

    CAS  PubMed  Article  Google Scholar 

  26. 26.

    Sturm, D. et al. Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma. Cancer Cell. 22, 425–437 (2012).

    CAS  PubMed  Article  Google Scholar 

  27. 27.

    Behjati, S. et al. Distinct H3F3A and H3F3B driver mutations define chondroblastoma and giant cell tumor of bone. Nat. Genet. 45, 1479–1482 (2013).

    CAS  PubMed  Article  Google Scholar 

  28. 28.

    Lu, C. et al. Histone H3K36 mutations promote sarcomagenesis through altered histone methylation landscape. Science 352, 844–849 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  29. 29.

    Mar, B. G. et al. Mutations in epigenetic regulators including SETD2 are gained during relapse in paediatric acute lymphoblastic leukaemia. Nat. Commun. 5, 3469 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  30. 30.

    Andersson, A. K. et al. IDH1 and IDH2 mutations in pediatric acute leukemia. Leukemia 25, 1570–1577 (2011).

    CAS  PubMed  Article  Google Scholar 

  31. 31.

    Ayton, P. M. & Cleary, M. L. Molecular mechanisms of leukemogenesis mediated by MLL fusion proteins. Oncogene 20, 5695–5707 (2001).

    CAS  PubMed  Article  Google Scholar 

  32. 32.

    Mack, S. C. et al. Epigenomic alterations define lethal CIMP-positive ependymomas of infancy. Nature 506, 445–450 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  33. 33.

    Bayliss, J. et al. Lowered H3K27me3 and DNA hypomethylation define poorly prognostic pediatric posterior fossa ependymomas. Sci. Transl. Med. 8, 366ra161 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  34. 34.

    Mack, S. C. et al. Therapeutic targeting of ependymoma as informed by oncogenic enhancer profiling. Nature 553, 101–105 (2018).

    CAS  PubMed  Article  Google Scholar 

  35. 35.

    Capper, D. et al. DNA methylation-based classification of central nervous system tumours. Nature 555, 469–474 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  36. 36.

    Koelsche, C. et al. Array-based DNA-methylation profiling in sarcomas with small blue round cell histology provides valuable diagnostic information. Mod. Pathol. 31, 1246–1256 (2018).

    CAS  PubMed  Article  Google Scholar 

  37. 37.

    Ford, A. M. et al. In utero rearrangements in the trithorax-related oncogene in infant leukaemias. Nature 363, 358–360 (1993).

    CAS  PubMed  Article  Google Scholar 

  38. 38.

    Greaves, M. F., Maia, A. T., Wiemels, J. L. & Ford, A. M. Leukemia in twins: lessons in natural history. Blood 102, 2321–2333 (2003).

    CAS  PubMed  Article  Google Scholar 

  39. 39.

    Gale, K. B. et al. Backtracking leukemia to birth: identification of clonotypic gene fusion sequences in neonatal blood spots. Proc. Natl Acad. Sci. USA 94, 13950–13954 (1997).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  40. 40.

    Wiemels, J. L. et al. Prenatal origin of acute lymphoblastic leukaemia in children. Lancet 354, 1499–1503 (1999).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  41. 41.

    Wiemels, J. L. et al. In utero origin of t(8;21) AML1-ETO translocations in childhood acute myeloid leukemia. Blood 99, 3801–3805 (2002).

    CAS  PubMed  Article  Google Scholar 

  42. 42.

    Hjalgrim, L. L. et al. Presence of clone-specific markers at birth in children with acute lymphoblastic leukaemia. Br. J. Cancer 87, 994–999 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  43. 43.

    McHale, C. M. et al. Prenatal origin of TEL-AML1-positive acute lymphoblastic leukemia in children born in California. Genes Chromosom. Cancer 37, 36–43 (2003).

    CAS  PubMed  Article  Google Scholar 

  44. 44.

    Mori, H. et al. Chromosome translocations and covert leukemic clones are generated during normal fetal development. Proc. Natl Acad. Sci. USA 99, 8242–8247 (2002).

    CAS  PubMed  Article  Google Scholar 

  45. 45.

    Hong, D. et al. Initiating and cancer-propagating cells in TEL-AML1-associated childhood leukemia. Science 319, 336–339 (2008).

    CAS  PubMed  Article  Google Scholar 

  46. 46.

    Böiers, C. et al. A human IPS model implicates embryonic B-myeloid fate restriction as developmental susceptibility to B acute lymphoblastic leukemia-associated ETV6-RUNX1. Dev. Cell 44, 362–377.e7 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  47. 47.

    Hitzler, J. K. & Zipursky, A. Origins of leukaemia in children with Down syndrome. Nat. Rev. Cancer 5, 11–20 (2005).

    CAS  PubMed  Article  Google Scholar 

  48. 48.

    Crispino, J. D. GATA1 mutations in Down syndrome: implications for biology and diagnosis of children with transient myeloproliferative disorder and acute megakaryoblastic leukemia. Pediatr. Blood. Cancer 44, 40–44 (2005).

    PubMed  Article  Google Scholar 

  49. 49.

    Krivtsov, A. V. et al. Cell of origin determines clinically relevant subtypes of MLL-rearranged AML. Leukemia 27, 852–860 (2013).

    CAS  PubMed  Article  Google Scholar 

  50. 50.

    Chen, W. et al. A murine Mll-AF4 knock-in model results in lymphoid and myeloid deregulation and hematologic malignancy. Blood 108, 669–677 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  51. 51.

    Ye, M. et al. Hematopoietic differentiation is required for initiation of acute myeloid leukemia. Cell Stem Cell 17, 611–623 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  52. 52.

    Shlush, L. I. et al. Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia. Nature 506, 328–333 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  53. 53.

    Sévenet, N. et al. Spectrum of hSNF5/INI1 somatic mutations in human cancer and genotype-phenotype correlations. Hum. Mol. Genet. 8, 2359–2368 (1999).

    PubMed  Article  Google Scholar 

  54. 54.

    Versteege, I. et al. Truncating mutations of hSNF5/INI1 in aggressive paediatric cancer. Nature 394, 203–206 (1998).

    CAS  PubMed  Article  Google Scholar 

  55. 55.

    Judkins, A. R. et al. INI1 protein expression distinguishes atypical teratoid/rhabdoid tumor from choroid plexus carcinoma. J. Neuropathol. Exp. Neurol. 64, 391–397 (2005).

    CAS  PubMed  Article  Google Scholar 

  56. 56.

    Guidi, C. J. et al. Disruption of Ini1 leads to peri-implantation lethality and tumorigenesis in mice. Mol. Cell. Biol. 21, 3598–3603 (2001).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  57. 57.

    Klochendler-Yeivin, A. et al. The murine SNF5/INI1 chromatin remodeling factor is essential for embryonic development and tumor suppression. EMBO Rep. 1, 500–506 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  58. 58.

    Roberts, C. W., Galusha, S. A., McMenamin, M. E., Fletcher, C. D. & Orkin, S. H. Haploinsufficiency of Snf5 (integrase interactor 1) predisposes to malignant rhabdoid tumors in mice. Proc. Natl Acad. Sci. USA 97, 13796–13800 (2000).

    CAS  PubMed  Article  Google Scholar 

  59. 59.

    Marshall, G. M. et al. The prenatal origins of cancer. Nat. Rev. Cancer 14, 277–289 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  60. 60.

    Maris, J. M. & Denny, C. T. Focus on embryonal malignancies. Cancer Cell 2, 447–450 (2002).

    CAS  PubMed  Article  Google Scholar 

  61. 61.

    Mackay, A. et al. Integrated molecular meta-analysis of 1,000 pediatric high-grade and diffuse intrinsic pontine glioma. Cancer Cell 32, 520–537.e5 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  62. 62.

    Yakovlev, P. I. The myelogenetic cycles of regional maturation of the brain. in Regional Development of the Brain in Early Life (ed. Minkowski, A.) 3–70 (Blackwell Scientific Publications, Oxford, 1967).

  63. 63.

    Lebel, C. et al. Diffusion tensor imaging of white matter tract evolution over the lifespan. Neuroimage 60, 340–352 (2012).

    CAS  PubMed  Article  Google Scholar 

  64. 64.

    Gibson, E. M., Geraghty, A. C. & Monje, M. Bad wrap: Myelin and myelin plasticity in health and disease. Dev. Neurobiol. 78, 123–135 (2018).

    PubMed  Article  Google Scholar 

  65. 65.

    Tate, M. C. et al. Postnatal growth of the human pons: a morphometric and immunohistochemical analysis. J. Comp. Neurol. 523, 449–462 (2015).

    PubMed  Article  Google Scholar 

  66. 66.

    Liu, C. et al. Mosaic analysis with double markers reveals tumor cell of origin in glioma. Cell 146, 209–221 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  67. 67.

    Alcantara Llaguno, S. R. et al. Adult Lineage-Restricted CNS Progenitors Specify Distinct Glioblastoma Subtypes. Cancer Cell 28, 429–440 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  68. 68.

    Qaddoumi, I., Sultan, I. & Gajjar, A. Outcome and prognostic features in pediatric gliomas: a review of 6212 cases from the Surveillance, Epidemiology, and End Results database. Cancer 115, 5761–5770 (2009).

    PubMed  PubMed Central  Article  Google Scholar 

  69. 69.

    Gibson, E. M. et al. Neuronal activity promotes oligodendrogenesis and adaptive myelination in the mammalian brain. Science 344, 1252304 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  70. 70.

    Mensch, S. et al. Synaptic vesicle release regulates myelin sheath number of individual oligodendrocytes in vivo. Nat. Neurosci. 18, 628–630 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  71. 71.

    Baraban, M., Mensch, S. & Lyons, D. A. Adaptive myelination from fish to man. Brain Res. 1641, 149–161 (2016). Pt A.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  72. 72.

    Hines, J. H., Ravanelli, A. M., Schwindt, R., Scott, E. K. & Appel, B. Neuronal activity biases axon selection for myelination in vivo. Nat. Neurosci. 18, 683–689 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  73. 73.

    McKenzie, I. A. et al. Motor skill learning requires active central myelination. Science 346, 318–322 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  74. 74.

    Mount, C. W. & Monje, M. Wrapped to adapt: experience-dependent myelination. Neuron 95, 743–756 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  75. 75.

    Venkatesh, H. S. et al. Neuronal activity promotes glioma growth through neuroligin-3 secretion. Cell 161, 803–816 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  76. 76.

    Venkatesh, H. S. et al. Targeting neuronal activity-regulated neuroligin-3 dependency in high-grade glioma. Nature 549, 533–537 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  77. 77.

    Knox, S. M. et al. Parasympathetic innervation maintains epithelial progenitor cells during salivary organogenesis. Science 329, 1645–1647 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  78. 78.

    Venkatesh, H. & Monje, M. Neuronal activity in ontogeny and oncology. Trends Cancer 3, 89–112 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  79. 79.

    Magnon, C. et al. Autonomic nerve development contributes to prostate cancer progression. Science 341, 1236361 (2013).

    PubMed  Article  Google Scholar 

  80. 80.

    Stopczynski, R. E. et al. Neuroplastic changes occur early in the development of pancreatic ductal adenocarcinoma. Cancer Res. 74, 1718–1727 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  81. 81.

    Hayakawa, Y. et al. Nerve growth factor promotes gastric tumorigenesis through aberrant cholinergic signaling. Cancer Cell. 31, 21–34 (2017).

    CAS  PubMed  Article  Google Scholar 

  82. 82.

    Peterson, S. C. et al. Basal cell carcinoma preferentially arises from stem cells within hair follicle and mechanosensory niches. Cell Stem Cell 16, 400–412 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  83. 83.

    Stupp, R. et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N. Engl. J. Med. 352, 987–996 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  84. 84.

    Cohen, K. J. et al. Temozolomide in the treatment of children with newly diagnosed diffuse intrinsic pontine gliomas: a report from the Children’s Oncology Group. Neuro-oncol. 13, 410–416 (2011).

    PubMed  PubMed Central  Article  Google Scholar 

  85. 85.

    Jalali, R. et al. Prospective evaluation of radiotherapy with concurrent and adjuvant temozolomide in children with newly diagnosed diffuse intrinsic pontine glioma. Int. J. Radiat. Oncol. Biol. Phys. 77, 113–118 (2010).

    CAS  PubMed  Article  Google Scholar 

  86. 86.

    Lashford, L. S. et al. Temozolomide in malignant gliomas of childhood: a United Kingdom Children’s Cancer Study Group and French Society for Pediatric Oncology Intergroup Study. J. Clin. Oncol. 20, 4684–4691 (2002).

    CAS  PubMed  Article  Google Scholar 

  87. 87.

    Grasso, C. S. et al. Functionally defined therapeutic targets in diffuse intrinsic pontine glioma. Nat. Med. 21, 555–559 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  88. 88.

    Hashizume, R. et al. Pharmacologic inhibition of histone demethylation as a therapy for pediatric brainstem glioma. Nat. Med. 20, 1394–1396 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  89. 89.

    Nagaraja, S. et al. Transcriptional dependencies in diffuse intrinsic pontine glioma. Cancer Cell 31, 635–652.e6 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  90. 90.

    Piunti, A. et al. Therapeutic targeting of polycomb and BET bromodomain proteins in diffuse intrinsic pontine gliomas. Nat. Med. 23, 493–500 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  91. 91.

    Mount, C. W. et al. Potent antitumor efficacy of anti-GD2 CAR T cells in H3-K27M+ diffuse midline gliomas. Nat. Med. 24, 572–579 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  92. 92.

    Brown, Z. Z. et al. Strategy for “detoxification” of a cancer-derived histone mutant based on mapping its interaction with the methyltransferase PRC2. J. Am. Chem. Soc. 136, 13498–13501 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  93. 93.

    Banerjee, A. et al. A phase I trial of the MEK inhibitor selumetinib (AZD6244) in pediatric patients with recurrent or refractory low-grade glioma: a Pediatric Brain Tumor Consortium (PBTC) study. Neuro-oncol. 19, 1135–1144 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  94. 94.

    Kondyli, M. et al. Trametinib for progressive pediatric low-grade gliomas. J. Neurooncol. 140, 435–444 (2018).

    CAS  PubMed  Article  Google Scholar 

  95. 95.

    Delattre, O. et al. The Ewing family of tumors—a subgroup of small-round-cell tumors defined by specific chimeric transcripts. N. Engl. J. Med. 331, 294–299 (1994).

    CAS  PubMed  Article  Google Scholar 

  96. 96.

    Zöllner, S. K. et al. Inhibition of the oncogenic fusion protein EWS-FLI1 causes G2-M cell cycle arrest and enhanced vincristine sensitivity in ‘Ewing’s sarcoma . Sci. Signal. 10, eaam8429 (2017).

    PubMed  Article  CAS  Google Scholar 

  97. 97.

    Maude, S. L. et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N. Engl. J. Med. 378, 439–448 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  98. 98.

    Murgai, M. et al. KLF4-dependent perivascular cell plasticity mediates pre-metastatic niche formation and metastasis. Nat. Med. 23, 1176–1190 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  99. 99.

    Gawade, P. L. et al. A systematic review of selected musculoskeletal late effects in survivors of childhood cancer. Curr. Pediatr. Rev. 10, 249–262 (2014).

    PubMed  Article  Google Scholar 

  100. 100.

    Green, J. L., Knight, S. J., McCarthy, M. & De Luca, C. R. Motor functioning during and following treatment with chemotherapy for pediatric acute lymphoblastic leukemia. Pediatr. Blood Cancer 60, 1261–1266 (2013).

    PubMed  Article  Google Scholar 

  101. 101.

    Ellenberg, L. et al. Neurocognitive status in long-term survivors of childhood CNS malignancies: a report from the Childhood Cancer Survivor Study. Neuropsychology 23, 705–717 (2009).

    PubMed  PubMed Central  Article  Google Scholar 

  102. 102.

    Pierson, C., Waite, E. & Pyykkonen, B. A meta-analysis of the neuropsychological effects of chemotherapy in the treatment of childhood cancer. Pediatr. Blood Cancer 63, 1998–2003 (2016).

    PubMed  Article  Google Scholar 

  103. 103.

    Parent, J. M., Tada, E., Fike, J. R. & Lowenstein, D. H. Inhibition of dentate granule cell neurogenesis with brain irradiation does not prevent seizure-induced mossy fiber synaptic reorganization in the rat. J. Neurosci. 19, 4508–4519 (1999).

    CAS  PubMed  Article  Google Scholar 

  104. 104.

    Tada, E., Yang, C., Gobbel, G. T., Lamborn, K. R. & Fike, J. R. Long-term impairment of subependymal repopulation following damage by ionizing irradiation. Exp. Neurol. 160, 66–77 (1999).

    CAS  PubMed  Article  Google Scholar 

  105. 105.

    Dietrich, J., Han, R., Yang, Y., Mayer-Pröschel, M. & Noble, M. CNS progenitor cells and oligodendrocytes are targets of chemotherapeutic agents in vitro and in vivo. J. Biol. 5, 22 (2006).

    PubMed  PubMed Central  Article  Google Scholar 

  106. 106.

    Eriksson, P. S. et al. Neurogenesis in the adult human hippocampus. Nat. Med. 4, 1313–1317 (1998).

    CAS  PubMed  Article  Google Scholar 

  107. 107.

    Monje, M. L. et al. Impaired human hippocampal neurogenesis after treatment for central nervous system malignancies. Ann. Neurol. 62, 515–520 (2007).

    PubMed  Article  Google Scholar 

  108. 108.

    Spalding, K. L. et al. Dynamics of hippocampal neurogenesis in adult humans. Cell 153, 1219–1227 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  109. 109.

    Monje, M. L., Mizumatsu, S., Fike, J. R. & Palmer, T. D. Irradiation induces neural precursor-cell dysfunction. Nat. Med. 8, 955–962 (2002).

    CAS  PubMed  Article  Google Scholar 

  110. 110.

    Monje, M. L., Toda, H. & Palmer, T. D. Inflammatory blockade restores adult hippocampal neurogenesis. Science 302, 1760–1765 (2003).

    CAS  PubMed  Article  Google Scholar 

  111. 111.

    Feng, X. et al. Colony-stimulating factor 1 receptor blockade prevents fractionated whole-brain irradiation-induced memory deficits. J. Neuroinflammation. 13, 215 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  112. 112.

    Feng, X., Liu, S., Chen, D., Rosi, S. & Gupta, N. Rescue of cognitive function following fractionated brain irradiation in a novel preclinical glioma model. eLife. 7, e38865 (2018).

    PubMed  PubMed Central  Article  Google Scholar 

  113. 113.

    Liddelow, S. A. et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541, 481–487 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  114. 114.

    Gibson, E. M. et al. Methotrexate chemotherapy induces persistent tri-glial dysregulation that underlies chemotherapy-related cognitive impairment. Cell 176, 43–55.e13 (2019).

    CAS  PubMed  Article  Google Scholar 

  115. 115.

    Schafer, D. P. et al. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron 74, 691–705 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  116. 116.

    Chung, W. S. et al. Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways. Nature 504, 394–400 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  117. 117.

    Dietrich, J. et al. Bone marrow drives central nervous system regeneration after radiation injury. J. Clin. Invest. 128, 281–293 (2018).

    PubMed  Article  Google Scholar 

  118. 118.

    Han, R. et al. Systemic 5-fluorouracil treatment causes a syndrome of delayed myelin destruction in the central nervous system. J. Biol. 7, 12 (2008).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  119. 119.

    Morioka, S. et al. Effects of chemotherapy on the brain in childhood: diffusion tensor imaging of subtle white matter damage. Neuroradiology 55, 1251–1257 (2013).

    PubMed  Article  Google Scholar 

  120. 120.

    Edelmann, M. N. et al. Diffusion tensor imaging and neurocognition in survivors of childhood acute lymphoblastic leukaemia. Brain 137, 2973–2983 (2014).

    PubMed  PubMed Central  Article  Google Scholar 

  121. 121.

    Hughes, E. G., Kang, S. H., Fukaya, M. & Bergles, D. E. Oligodendrocyte progenitors balance growth with self-repulsion to achieve homeostasis in the adult brain. Nat. Neurosci. 16, 668–676 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  122. 122.

    Acharya, M. M. et al. Stem cell transplantation reverses chemotherapy-induced cognitive dysfunction. Cancer Res. 75, 676–686 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  123. 123.

    Andres, A. L., Gong, X., Di, K. & Bota, D. A. Low-doses of cisplatin injure hippocampal synapses: a mechanism for ‘chemo’ brain? Exp. Neurol. 255, 137–144 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

Download references

Acknowledgements

The authors extend special thanks to S. Knemeyer for illustrations, to A. Groves for help with Supplementary Table 1 and to K. E. Warren for helpful input on Box 2, Challenges in clinical trials in childhood cancer. The authors acknowledge funding from the Career Award for Medical Scientist from Burroughs Wellcome Fund (M.G.F.), Solving Kids’ Cancer (M.G.F.), The Cure Starts Now Foundation and DIPG Collaborative (M.G.F. and M.M.), National Institutes of Neurological Disorders and Stroke (R01NS092597 to M.M.), National Institutes of Health (DP1NS111132 to M.M.), Abbie’s Army (M.M.), McKenna Claire Foundation (M.M.), Unravel Pediatric Cancer Foundation (M.M.), Alex’s Lemonade Stand Foundation (M.G.F. and M.M.), Maternal and Child Health Research Institute at Stanford (M.M.) and the Anne T. and Robert M. Bass Endowed Faculty Scholarship in Pediatric Cancer and Blood Diseases (M.M.).

Author information

Affiliations

Authors

Corresponding author

Correspondence to Michelle Monje.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Filbin, M., Monje, M. Developmental origins and emerging therapeutic opportunities for childhood cancer. Nat Med 25, 367–376 (2019). https://doi.org/10.1038/s41591-019-0383-9

Download citation

Further reading