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Acute lymphoblastic leukemia

Hedgehog pathway mutations drive oncogenic transformation in high-risk T-cell acute lymphoblastic leukemia

Leukemia volume 32, pages 2126–2137 (2018)Cite this article

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Abstract

The role of Hedgehog signaling in normal and malignant T-cell development is controversial. Recently, Hedgehog pathway mutations have been described in T-ALL, but whether mutational activation of Hedgehog signaling drives T-cell transformation is unknown, hindering the rationale for therapeutic intervention. Here, we show that Hedgehog pathway mutations predict chemotherapy resistance in human T-ALL, and drive oncogenic transformation in a zebrafish model of the disease. We found Hedgehog pathway mutations in 16% of 109 childhood T-ALL cases, most commonly affecting its negative regulator PTCH1. Hedgehog mutations were associated with resistance to induction chemotherapy (P = 0.009). Transduction of wild-type PTCH1 into PTCH1-mutant T-ALL cells induced apoptosis (P = 0.005), a phenotype that was reversed by downstream Hedgehog pathway activation (P = 0.007). Transduction of most mutant PTCH1, SUFU, and GLI alleles into mammalian cells induced aberrant regulation of Hedgehog signaling, indicating that these mutations are pathogenic. Using a CRISPR/Cas9 system for lineage-restricted gene disruption in transgenic zebrafish, we found that ptch1 mutations accelerated the onset of notch1-induced T-ALL (P = 0.0001), and pharmacologic Hedgehog pathway inhibition had therapeutic activity. Thus, Hedgehog-activating mutations are driver oncogenic alterations in high-risk T-ALL, providing a molecular rationale for targeted therapy in this disease.

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References

  1. Briscoe J, Therond PP. The mechanisms of Hedgehog signalling and its roles in development and disease. Nat Rev Mol Cell Biol. 2013;14:416–29.

    Article  PubMed  Google Scholar 

  2. Sharpe HJ, Wang W, Hannoush RN, de Sauvage FJ. Regulation of the oncoprotein Smoothened by small molecules. Nat Chem Biol. 2015;11:246–55.

    Article  CAS  PubMed  Google Scholar 

  3. Duman-Scheel M, Weng L, Xin S, Du W. Hedgehog regulates cell growth and proliferation by inducing Cyclin D and Cyclin E. Nature. 2002;417:299–304.

    Article  CAS  PubMed  Google Scholar 

  4. Johnson RL, Rothman AL, Xie J, Goodrich LV, Bare JW, Bonifas JM, et al. Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Science. 1996;272:1668–71.

    Article  CAS  PubMed  Google Scholar 

  5. Hahn H, Wicking C, Zaphiropoulous PG, Gailani MR, Shanley S, Chidambaram A, et al. Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell. 1996;85:841–51.

    Article  CAS  PubMed  Google Scholar 

  6. Stone DM, Hynes M, Armanini M, Swanson TA, Gu Q, Johnson RL, et al. The tumour-suppressor gene patched encodes a candidate receptor for Sonic hedgehog. Nature. 1996;384:129–34.

    Article  CAS  PubMed  Google Scholar 

  7. Goodrich LV, Milenkovic L, Higgins KM, Scott MP. Altered neural cell fates and medulloblastoma in mouse patched mutants. Science. 1997;277:1109–13.

    Article  CAS  PubMed  Google Scholar 

  8. Hahn H, Wojnowski L, Zimmer AM, Hall J, Miller G, Zimmer A. Rhabdomyosarcomas and radiation hypersensitivity in a mouse model of Gorlin syndrome. Nat Med. 1998;4:619–22.

    Article  CAS  PubMed  Google Scholar 

  9. Hettmer S, Teot LA, Kozakewich H, Werger AM, Davies KJ, Fletcher CD, et al. Myogenic tumors in nevoid Basal cell carcinoma syndrome. J Pediatr Hematol Oncol. 2015;37:147–9.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Drakopoulou E, Outram SV, Rowbotham NJ, Ross SE, Furmanski AL, Saldana JI, et al. Non-redundant role for the transcription factor Gli1 at multiple stages of thymocyte development. Cell Cycle. 2010;9:4144–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. El Andaloussi A, Graves S, Meng F, Mandal M, Mashayekhi M, Aifantis I. Hedgehog signaling controls thymocyte progenitor homeostasis and differentiation in the thymus. Nat Immunol. 2006;7:418–26.

    Article  CAS  PubMed  Google Scholar 

  12. Furmanski AL, Saldana JI, Rowbotham NJ, Ross SE, Crompton T. Role of Hedgehog signalling at the transition from double-positive to single-positive thymocyte. Eur J Immunol. 2012;42:489–99.

    Article  CAS  PubMed  Google Scholar 

  13. Outram SV, Hager-Theodorides AL, Shah DK, Rowbotham NJ, Drakopoulou E, Ross SE, et al. Indian hedgehog (Ihh) both promotes and restricts thymocyte differentiation. Blood. 2009;113:2217–28.

    Article  CAS  PubMed  Google Scholar 

  14. Rowbotham NJ, Hager-Theodorides AL, Furmanski AL, Ross SE, Outram SV, Dessens JT, et al. Sonic hedgehog negatively regulates pre-TCR-induced differentiation by a Gli2-dependent mechanism. Blood. 2009;113:5144–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Gao J, Graves S, Koch U, Liu S, Jankovic V, Buonamici S, et al. Hedgehog signaling is dispensable for adult hematopoietic stem cell function. Cell Stem Cell. 2009;4:548–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Hofmann I, Stover EH, Cullen DE, Mao J, Morgan KJ, Lee BH, et al. Hedgehog signaling is dispensable for adult murine hematopoietic stem cell function and hematopoiesis. Cell Stem Cell. 2009;4:559–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Dagklis A, Pauwels D, Lahortiga I, Geerdens E, Bittoun E, Cauwelier B, et al. Hedgehog pathway mutations in T-cell acute lymphoblastic leukemia. Haematologica. 2015;100:e102–5.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Dagklis A, Demeyer S, De Bie J, Radaelli E, Pauwels D, Degryse S, et al. Hedgehog pathway activation in T-cell acute lymphoblastic leukemia predicts response to SMO and GLI1 inhibitors. Blood. 2016;128:2642–54.

    Article  CAS  PubMed  Google Scholar 

  19. Sekulic A, Migden MR, Oro AE, Dirix L, Lewis KD, Hainsworth JD, et al. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med. 2012;366:2171–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Von Hoff DD, LoRusso PM, Rudin CM, Reddy JC, Yauch RL, Tibes R, et al. Inhibition of the hedgehog pathway in advanced basal-cell carcinoma. N Engl J Med. 2009;361:1164–72.

    Article  Google Scholar 

  21. Robinson GW, Orr BA, Wu G, Gururangan S, Lin T, Qaddoumi I, et al. Vismodegib Exerts Targeted Efficacy Against Recurrent Sonic Hedgehog-Subgroup Medulloblastoma: Results From Phase II Pediatric Brain Tumor Consortium Studies PBTC-025B and PBTC-032. J Clin Oncol. 2015;33:2646–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Tang JY, Ally MS, Chanana AM, Mackay-Wiggan JM, Aszterbaum M, Lindgren JA, et al. Inhibition of the hedgehog pathway in patients with basal-cell nevus syndrome: final results from the multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol. 2016;17:1720–31.

    Article  CAS  PubMed  Google Scholar 

  23. LoRusso PM, Rudin CM, Reddy JC, Tibes R, Weiss GJ, Borad MJ, et al. Phase I trial of hedgehog pathway inhibitor vismodegib (GDC-0449) in patients with refractory, locally advanced or metastatic solid tumors. Clin Cancer Res. 2011;17:2502–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Catenacci DV, Junttila MR, Karrison T, Bahary N, Horiba MN, Nattam SR, et al. Randomized Phase Ib/II Study of Gemcitabine Plus Placebo or Vismodegib, a Hedgehog Pathway Inhibitor, in Patients With Metastatic Pancreatic Cancer. J Clin Oncol. 2015;33:4284–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Kaye SB, Fehrenbacher L, Holloway R, Amit A, Karlan B, Slomovitz B, et al. A phase II, randomized, placebo-controlled study of vismodegib as maintenance therapy in patients with ovarian cancer in second or third complete remission. Clin Cancer Res. 2012;18:6509–18.

    Article  CAS  PubMed  Google Scholar 

  26. Rodon J, Tawbi HA, Thomas AL, Stoller RG, Turtschi CP, Baselga J, et al. A phase I, multicenter, open-label, first-in-human, dose-escalation study of the oral smoothened inhibitor Sonidegib (LDE225) in patients with advanced solid tumors. Clin Cancer Res. 2014;20:1900–9.

    Article  CAS  PubMed  Google Scholar 

  27. Place AE, Stevenson KE, Vrooman LM, Harris MH, Hunt SK, O’Brien JE, et al. Intravenous pegylated asparaginase versus intramuscular native Escherichia coli L-asparaginase in newly diagnosed childhood acute lymphoblastic leukaemia (DFCI 05-001): a randomised, open-label phase 3 trial. Lancet Oncol. 2015;16:1677–90.

    Article  CAS  PubMed  Google Scholar 

  28. Winter SS, Dunsmore KP, Devidas M, Eisenberg N, Asselin BL, Wood BL, et al. Safe integration of nelarabine into intensive chemotherapy in newly diagnosed T-cell acute lymphoblastic leukemia: Children’s Oncology Group Study AALL0434. Pediatr Blood Cancer. 2015;62:1176–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. So PL, Langston AW, Daniallinia N, Hebert JL, Fujimoto MA, Khaimskiy Y, et al. Long-term establishment, characterization and manipulation of cell lines from mouse basal cell carcinoma tumors. Exp Dermatol. 2006;15:742–50.

    Article  CAS  PubMed  Google Scholar 

  30. Aszterbaum M, Epstein J, Oro A, Douglas V, LeBoit PE, Scott MP, et al. Ultraviolet and ionizing radiation enhance the growth of BCCs and trichoblastomas in patched heterozygous knockout mice. Nat Med. 1999;5:1285–91.

    Article  CAS  PubMed  Google Scholar 

  31. Kenney AM, Cole MD, Rowitch DH. Nmyc upregulation by sonic hedgehog signaling promotes proliferation in developing cerebellar granule neuron precursors. Development. 2003;130:15–28.

    Article  CAS  PubMed  Google Scholar 

  32. Ferrando AA, Neuberg DS, Staunton J, Loh ML, Huard C, Raimondi SC, et al. Gene expression signatures define novel oncogenic pathways in T cell acute lymphoblastic leukemia. Cancer Cell. 2002;1:75–87.

    Article  CAS  PubMed  Google Scholar 

  33. Liu Y, Easton J, Shao Y, Maciaszek J, Wang Z, Wilkinson MR, et al. The genomic landscape of pediatric and young adult T-lineage acute lymphoblastic leukemia. Nat Genet. 2017;49:1211–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Gutierrez A, Grebliunaite R, Feng H, Kozakewich E, Zhu S, Guo F, et al. Pten mediates Myc oncogene dependence in a conditional zebrafish model of T cell acute lymphoblastic leukemia. J Exp Med. 2011;208:1595–603.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Reynolds C, Roderick JE, LaBelle JL, Bird G, Mathieu R, Bodaar K, et al. Repression of BIM mediates survival signaling by MYC and AKT in high-risk T-cell acute lymphoblastic leukemia. Leukemia. 2014;28:1819–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Lindstrom E, Shimokawa T, Toftgard R, Zaphiropoulos PG. PTCH mutations: distribution and analyses. Hum Mutat. 2006;27:215–9.

    Article  CAS  PubMed  Google Scholar 

  37. Stenson PD, Mort M, Ball EV, Evans K, Hayden M, Heywood S, et al. The Human Gene Mutation Database: towards a comprehensive repository of inherited mutation data for medical research, genetic diagnosis and next-generation sequencing studies. Hum Genet. 2017;136:665–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Taipale J, Chen JK, Cooper MK, Wang B, Mann RK, Milenkovic L, et al. Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine. Nature. 2000;406:1005–9.

    Article  CAS  PubMed  Google Scholar 

  39. Chen J, Jette C, Kanki JP, Aster JC, Look AT, Griffin JD. NOTCH1-induced T-cell leukemia in transgenic zebrafish. Leukemia. 2007;21:462–71.

    Article  PubMed  Google Scholar 

  40. Blackburn JS, Liu S, Raiser DM, Martinez SA, Feng H, Meeker ND, et al. Notch signaling expands a pre-malignant pool of T-cell acute lymphoblastic leukemia clones without affecting leukemia-propagating cell frequency. Leukemia. 2012;26:2069–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Koudijs MJ, den Broeder MJ, Keijser A, Wienholds E, Houwing S, van Rooijen EM, et al. The zebrafish mutants dre, uki, and lep encode negative regulators of the hedgehog signaling pathway. PLoS Genet. 2005;1:e19.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Sadelain M, Papapetrou EP, Bushman FD. Safe harbours for the integration of new DNA in the human genome. Nat Rev Cancer. 2011;12:51–8.

    Article  PubMed  Google Scholar 

  43. Robarge KD, Brunton SA, Castanedo GM, Cui Y, Dina MS, Goldsmith R, et al. GDC-0449-a potent inhibitor of the hedgehog pathway. Bioorg Med Chem Lett. 2009;19:5576–81.

    Article  CAS  PubMed  Google Scholar 

  44. Neumann CJ, Grandel H, Gaffield W, Schulte-Merker S, Nusslein-Volhard C. Transient establishment of anteroposterior polarity in the zebrafish pectoral fin bud in the absence of sonic hedgehog activity. Development. 1999;126:4817–26.

    CAS  PubMed  Google Scholar 

  45. Goldberg JM, Silverman LB, Levy DE, Dalton VK, Gelber RD, Lehmann L, et al. Childhood T-cell acute lymphoblastic leukemia: the Dana-Farber Cancer Institute acute lymphoblastic leukemia consortium experience. J Clin Oncol. 2003;21:3616–22.

    Article  PubMed  Google Scholar 

  46. Marks DI, Paietta EM, Moorman AV, Richards SM, Buck G, DeWald G, et al. T-cell acute lymphoblastic leukemia in adults: clinical features, immunophenotype, cytogenetics, and outcome from the large randomized prospective trial (UKALL XII/ECOG 2993). Blood. 2009;114:5136–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Hunger SP, Lu X, Devidas M, Camitta BM, Gaynon PS, Winick NJ, et al. Improved survival for children and adolescents with acute lymphoblastic leukemia between 1990 and 2005: a report from the children’s oncology group. J Clin Oncol. 2012;30:1663–9.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Pui CH, Campana D, Pei D, Bowman WP, Sandlund JT, Kaste SC, et al. Treating childhood acute lymphoblastic leukemia without cranial irradiation. N Engl J Med. 2009;360:2730–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Ko RH, Ji L, Barnette P, Bostrom B, Hutchinson R, Raetz E, et al. Outcome of patients treated for relapsed or refractory acute lymphoblastic leukemia: a Therapeutic Advances in Childhood Leukemia Consortium study. J Clin Oncol. 2010;28:648–54.

    Article  PubMed  Google Scholar 

  50. Schrappe M, Hunger SP, Pui CH, Saha V, Gaynon PS, Baruchel A, et al. Outcomes after induction failure in childhood acute lymphoblastic leukemia. N Engl J Med. 2012;366:1371–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Fielding AK, Richards SM, Chopra R, Lazarus HM, Litzow MR, Buck G, et al. Outcome of 609 adults after relapse of acute lymphoblastic leukemia (ALL); an MRC UKALL12/ECOG 2993 study. Blood. 2007;109:944–50.

    Article  CAS  PubMed  Google Scholar 

  52. Zahreddine HA, Culjkovic-Kraljacic B, Assouline S, Gendron P, Romeo AA, Morris SJ, et al. The sonic hedgehog factor GLI1 imparts drug resistance through inducible glucuronidation. Nature. 2014;511:90–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Vo TT, Ryan J, Carrasco R, Neuberg D, Rossi DJ, Stone RM, et al. Relative mitochondrial priming of myeloblasts and normal HSCs determines chemotherapeutic success in AML. Cell . 2012;151:344–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Bhola PD, Mar BG, Lindsley RC, Ryan JA, Hogdal LJ, Vo TT, et al. Functionally identifiable apoptosis-insensitive subpopulations determine chemoresistance in acute myeloid leukemia. J Clin Invest. 2016;126:3827–36.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Ni Chonghaile T, Sarosiek KA, Vo TT, Ryan JA, Tammareddi A, Moore Vdel G, et al. Pretreatment mitochondrial priming correlates with clinical response to cytotoxic chemotherapy. Science. 2011;334:1129–33.

    Article  PubMed  Google Scholar 

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Acknowledgements

We thank Julien Ablain for the pCS2-Cas9, pDest-Tol2-CG2-U6-gRNA, pME-MCS-zfCas9-T2A-GFP, and p3E-polyA vectors. We thank Christine Reynolds and Oscar Calzada for technical assistance; and Sofie Peirs, Bjorn Menten, and Pieter Van Vlierberghe for the array CGH analysis. We thank Jessica Blackburn for the rag2-notch1aICD vector; and Jae Cho for the basal cell carcinoma cell line, ASZ001. We are grateful to the patients and families who provided samples for these studies. This work was supported by NIH R01 CA193651 (AG) and the Boston Children’s Hospital Translational Research Program (AG). The Children’s Oncology Group work was supported by U10 CA98543 (COG Chair’s grant), U10 CA98413 (COG Statistical Center), U24 CA114766 (COG Specimen Banking), U10 CA 180886 (COG Operations Center), and U10 CA 180899 (COG Statistics and Data Center). MB is supported by the Children’s Leukemia Research Association, Inc. SPH is the Jeffrey E. Perelman Distinguished Chair in the Department of Pediatrics, Children’s Hospital of Philadelphia. AG is supported by an Investigatorship at Boston Children’s Hospital.

Author contributions:

MAB, ZWL, and AG conceived the project, designed and performed experiments, interpreted data, and wrote the manuscript. ART and MD performed the targeted exon sequencing and analysis. MAB, GPP, and AG analyzed targeted exon sequencing, RNA sequencing and array CGH data. MAB, EAS, and NY performed and interpreted experiments. KES and DSN performed statistical analyses and interpreted data. KES, DSN, SPH, MLL, SSW, KPD, MD, LBS, and SES aided in data collection of primary patient samples, and in analysis and interpretation of data. All authors aided in critical revision and approval of the submitted manuscript.

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Authors and Affiliations

  1. Division of Hematology/Oncology, Boston Children’s Hospital, Boston, MA, 02115, USA

    Melissa A. Burns, Zi Wei Liao, Natsuko Yamagata, Gayle P. Pouliot, Emily A. Silverman, Lewis B. Silverman, Stephen E. Sallan & Alejandro Gutierrez

  2. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA

    Melissa A. Burns, Gayle P. Pouliot, Lewis B. Silverman, Stephen E. Sallan & Alejandro Gutierrez

  3. Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA

    Kristen E. Stevenson & Donna S. Neuberg

  4. Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, MA, 02215, USA

    Aaron R. Thorner & Matthew Ducar

  5. Division of Oncology and the Center for Childhood Cancer Research, The Children’s Hospital of Philadelphia and the Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA

    Stephen P. Hunger

  6. Department of Pediatrics, University of California San Francisco, San Francisco, CA, 94158, USA

    Mignon L. Loh

  7. Department of Pediatrics, University of New Mexico Health Sciences Center, Albuquerque, NM, 87131, USA

    Stuart S. Winter

  8. Division of Oncology, University of Virginia Children’s Hospital, Charlottesville, VA, 22903, USA

    Kimberly P. Dunsmore

  9. Department of Laboratory Medicine, University of Washington, Seattle, 98195, WA, USA

    Brent Wood

  10. Department of Biostatistics, University of Florida, Gainesville, FL, 32611, USA

    Meenakshi Devidas

  11. Department of Pathology, Boston Children’s Hospital, Boston, MA, 02115, USA

    Marian H. Harris

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  1. Melissa A. Burns
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Burns, M.A., Liao, Z.W., Yamagata, N. et al. Hedgehog pathway mutations drive oncogenic transformation in high-risk T-cell acute lymphoblastic leukemia. Leukemia 32, 2126–2137 (2018). https://doi.org/10.1038/s41375-018-0097-x

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