Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Acute myeloid leukemia

Genetic mechanisms of primary chemotherapy resistance in pediatric acute myeloid leukemia

Leukemia volume 33, pages 1934–1943 (2019)Cite this article

Subjects

Abstract

Acute myeloid leukemias (AML) are characterized by mutations of tumor suppressor and oncogenes, involving distinct genes in adults and children. While certain mutations have been associated with the increased risk of AML relapse, the genomic landscape of primary chemotherapy-resistant AML is not well defined. As part of the TARGET initiative, we performed whole-genome DNA and transcriptome RNA and miRNA sequencing analysis of pediatric AML with failure of induction chemotherapy. We identified at least three genetic groups of patients with induction failure, including those with NUP98 rearrangements, somatic mutations of WT1 in the absence of apparent NUP98 mutations, and additional recurrent variants including those in KMT2C and MLLT10. Comparison of specimens before and after chemotherapy revealed distinct and invariant gene expression programs. While exhibiting overt therapy resistance, these leukemias nonetheless showed diverse forms of clonal evolution upon chemotherapy exposure. This included selection for mutant alleles of FRMD8, DHX32, PIK3R1, SHANK3, MKLN1, as well as persistence of WT1 and TP53 mutant clones, and elimination of FLT3, PTPN11, and NRAS mutant clones. These findings delineate genetic mechanisms of primary chemotherapy resistance in pediatric AML, which should inform improved approaches for its diagnosis and therapy.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Rasche M, Zimmermann M, Borschel L, Bourquin JP, Dworzak M, Klingebiel T, et al. Successes and challenges in the treatment of pediatric acute myeloid leukemia: a retrospective analysis of the AML-BFM trials from 1987 to 2012. Leukemia. 2018;32:2167–77.

    Article  Google Scholar 

  2. Gamis AS, Alonzo TA, Meschinchi S, Sung L, Berbing RB, Raimondi SC, et al. Gemtuzumab Ozogamicin in children and adolescents with de novo acute myeloid leukemia improves event-free survival by reducing relapse risk: results from the randomized phase III chidren’s oncology group trial AAML0531. J Clin Oncol. 2014;32:3021–32.

    Article  CAS  Google Scholar 

  3. Ley TJ, Ding L, Walter MJ, McLellan MD, Lamprecht T, Larson DE, et al. DNMT3A mutations in acute myeloid leukemia. N Engl J Med. 2010;363:2424–33.

    Article  CAS  Google Scholar 

  4. Mardis ER, Ding L, Dooling DJ, Larson DE, McLellan MD, Chen K, et al. Recurring mutations found by sequencing an acute myeloid leukemia genome. N Engl J Med. 2009;361:1058–66.

    Article  CAS  Google Scholar 

  5. Papaemmanuil E, Gerstung M, Bullinger L, Gaidzik VI, Paschka P, Roberts ND, et al. Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med. 2016;374:2209–21.

    Article  CAS  Google Scholar 

  6. Ding L, Ley TJ, Larson DE, Miller CA, Koboldt DC, Welch JS, et al. Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing. Nature. 2012;481:506–10.

    Article  CAS  Google Scholar 

  7. Farrar JE, Schuback HL, Ries RE, Wai D, Hampton OA, Trevino LR, et al. Genomic profiling of pediatric acute myeloid leukemia reveals a changing mutational landscape from disease diagnosis to relapse. Cancer Res. 2016;76:2197–205.

    Article  CAS  Google Scholar 

  8. Klco JM, Miller CA, Griffith M, Petti A, Spencer DH, Ketkar-Kulkarni S, et al. Association between mutation clearance after induction therapy and outcomes in acute myeloid leukemia. JAMA. 2015;314:811–22.

    Article  CAS  Google Scholar 

  9. Brown FC, Cifani P, Drill E, He J, Still E, Zhong S, et al. Genomics of primary chemoresistance and remission induction failure in paediatric and adult acute myeloid leukaemia. Br J Haematol. 2017;176:86–91.

    Article  CAS  Google Scholar 

  10. Brown FC, Still E, Koche RP, Yim CY, Takao S, Cifani P, et al. MEF2C phosphorylation is required for chemotherapy resistance in acute myeloid leukemia. Cancer Discov. 2018;8:478–97.

    Article  CAS  Google Scholar 

  11. Laszlo GS, Alonzo TA, Gudgeon CJ, Harrington KH, Kentsis A, Gerbing RB, et al. High expression of myocyte enhancer factor 2C (MEF2C) is associated with adverse-risk features and poor outcome in pediatric acute myeloid leukemia: a report from the Children’s Oncology Group. J Hematol Oncol. 2015;8:115.

    Article  Google Scholar 

  12. Bolouri H, Farrar JE, Triche T Jr., Ries RE, Lim EL, Alonzo TA, et al. The molecular landscape of pediatric acute myeloid leukemia reveals recurrent structural alterations and age-specific mutational interactions. Nat Med. 2018;24:103–12.

    Article  CAS  Google Scholar 

  13. Cancer Genome Atlas Research N, Ley TJ, Miller C, Ding L, Raphael BJ, Mungall AJ, et al. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013;368:2059–74.

    Article  Google Scholar 

  14. Ando K, Tsushima H, Matsuo E, Horio K, Tominaga-Sato S, Imanishi D, et al. Mutations in the nucleolar phosphoprotein, nucleophosmin, promote the expression of the oncogenic transcription factor MEF/ELF4 in leukemia cells and potentiates transformation. J Biol Chem. 2013;288:9457–67.

    Article  CAS  Google Scholar 

  15. Hollink IH, van den Heuvel-Eibrink MM, Arentsen-Peters ST, Pratcorona M, Abbas S, Kuipers JE, et al. NUP98/NSD1 characterizes a novel poor prognostic group in acute myeloid leukemia with a distinct HOX gene expression pattern. Blood. 2011;118:3645–56.

    Article  CAS  Google Scholar 

  16. Ostronoff F, Othus M, Gerbing RB, Loken MR, Raimondi SC, Hirsch BA, et al. NUP98/NSD1 and FLT3/ITD coexpression is more prevalent in younger AML patients and leads to induction failure: a COG and SWOG report. Blood. 2014;124:2400–7.

    Article  CAS  Google Scholar 

  17. da Silva-Coelho P, Kroeze LI, Yoshida K, Koorenhof-Scheele TN, Knops R, van de Locht LT, et al. Clonal evolution in myelodysplastic syndromes. Nat Commun. 2017;8:15099.

    Article  Google Scholar 

  18. Lavallee VP, Lemieux S, Boucher G, Gendron P, Boivin I, Girard S, et al. Identification of MYC mutations in acute myeloid leukemias with NUP98-NSD1 translocations. Leukemia. 2016;30:1621–4.

    Article  CAS  Google Scholar 

  19. Miyagi T, Ahuja H, Kubota T, et al. Expression of the candidate Wilms-tumor gene, Wt1, in human leukemia cells. Leukemia. 1993;7:970–7.

    CAS  PubMed  Google Scholar 

  20. Bergmann L, Miething C, Maurer U, et al. High levels of Wilms’ tumor gene (wt1) mRNA in acute myeloid leukemias are associated with a worse long-term outcome. Blood. 1997;90:1217–25.

    CAS  PubMed  Google Scholar 

  21. King-Underwood L, Renshaw J, PritchardJones K. Mutations in the Wilms’ tumor gene WT1 in leukemias. Blood. 1996;87:2171–9.

    CAS  PubMed  Google Scholar 

  22. Gutierrez A, Kentsis A, Sanda T, Holmfeldt L, Chen SC, Zhang J, et al. The BCL11B tumor suppressor is mutated across the major molecular subtypes of T-cell acute lymphoblastic leukemia. Blood. 2011;118:4169–73.

    Article  CAS  Google Scholar 

  23. Gutierrez A, Kentsis A. Acute myeloid/T-lymphoblastic leukaemia (AMTL): a distinct category of acute leukaemias with common pathogenesis in need of improved therapy. Br J Haematol. 2018;180:919–24.

    Article  CAS  Google Scholar 

  24. Chen C, Liu Y, Rappaport AR, Kitzing T, Schultz N, Zhao Z, et al. MLL3 is a haploinsufficient 7q tumor suppressor in acute myeloid leukemia. Cancer Cell. 2014;25:652–65.

    Article  Google Scholar 

  25. Brandimarte L, Pierini V, Di Giacomo D, Borga C, Nozza F, Gorello P, et al. New MLLT10 gene recombinations in pediatric T-acute lymphoblastic leukemia. Blood. 2013;121:5064–7.

    Article  CAS  Google Scholar 

  26. Lavallee P, Gendron P, Lemieux S, D’Angelo G, Hebert J, Sauvageau G. EVI1-rearranged acute myeloid leukemias are characterized by distinct molecular alterations. Blood. 2015;125:140–3.

    Article  CAS  Google Scholar 

  27. Li H, Rao Q, Yu P, Chen S, Li Z, et al. Expression of MPL in leukemia stem cells and its role in stemness maintenance. Blood. 2016;128:1723.

    Article  Google Scholar 

  28. Volinia S, Calin GA, Liu CG, Ambs S, Cimmino A, Petrocca F, et al. A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci USA. 2006;103:2257–61.

    Article  CAS  Google Scholar 

  29. Ovcharenko D, Stolzel F, Poitz D, Fierro F, Schaich M, Neubauer A, et al. miR-10a overexpression is associated with NPM1 mutations and MDM4 downregulation in intermediate-risk acute myeloid leukemia. Exp Hematol. 2011;39:1030–42 e7.

    Article  CAS  Google Scholar 

  30. Huang JW, Wang Y, Dhillon KK, Calses P, Villegas E, Mitchell PS, et al. Systematic screen identifies miRNAs that target RAD51 and RAD51D to enhance chemosensitivity. Mol Cancer Res. 2013;11:1564–73.

    Article  CAS  Google Scholar 

  31. Liu X, Liao W, Peng H, Luo X, Luo Z, Jiang H, et al. miR-181a promotes G1/S transition and cell proliferation in pediatric acute myeloid leukemia by targeting ATM. J Cancer Res Clin Oncol. 2016;142:77–87.

    Article  CAS  Google Scholar 

  32. Gabra MM, Salmena L. MicroRNAs and acute myeloid leukemia chemoresistance: a mechanistic overview. Front Oncol. 2017;7:255.

    Article  Google Scholar 

  33. Kunzel U, Grieve AG, Meng Y, Sieber B, Cowley SA, Freeman M. FRMD8 promotes inflammatory and growth factor signalling by stabilising the iRhom/ADAM17 sheddase complex. eLife. 2018;7:e35012.

    Article  Google Scholar 

  34. Kategaya LS, Changkakoty B, Biechele T, Conrad WH, Kaykas A, Dasgupta R, et al. Bili inhibits Wnt/beta-catenin signaling by regulating the recruitment of axin to LRP6. PLoS ONE. 2009;4:e6129.

    Article  Google Scholar 

  35. Bou Samra E, Klein B, Commes T, Moreaux J. Development of gene expression-based risk score in cytogenetically normal acute myeloid leukemia patients. Oncotarget. 2012;3:824–32.

    PubMed  PubMed Central  Google Scholar 

  36. Abu-Duhier FM, Goodeve AC, Wilson GA, Gari MA, Peake IR, Rees DC, et al. FLT3 internal tandem duplication mutations in adult acute myeloid leukaemia define a high-risk group. Br J Haematol. 2000;111:190–5.

    Article  CAS  Google Scholar 

  37. Meshinchi S, Woods WG, Stirewalt DL, Sweetser DA, Buckley JD, Tjoa TK, et al. Prevalence and prognostic significance of Flt3 internal tandem duplication in pediatric acute myeloid leukemia. Blood. 2001;97:89–94.

    Article  CAS  Google Scholar 

  38. Thiede C, Steudel C, Mohr B, Schaich M, Schakel U, Platzbecker U, et al. Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood. 2002;99:4326–35.

    Article  CAS  Google Scholar 

  39. Schlenk RF, Kayser S, Bullinger L, Kobbe G, Casper J, Ringhoffer M, et al. Differential impact of allelic ratio and insertion site in FLT3-ITD-positive AML with respect to allogeneic transplantation. Blood. 2014;124:3441–9.

    Article  CAS  Google Scholar 

  40. Garg M, Nagata Y, Kanojia D, Mayakonda A, Yoshida K, Haridas Keloth S, et al. Profiling of somatic mutations in acute myeloid leukemia with FLT3-ITD at diagnosis and relapse. Blood. 2015;126:2491–501.

    Article  CAS  Google Scholar 

  41. Visani G, Ferrara F, Di Raimondo F, Loscocco F, Fuligni F, Paolini S, et al. Low-dose lenalidomide plus cytarabine in very elderly, unfit acute myeloid leukemia patients: final result of a phase II study. Leuk Res. 2017;62:77–83.

    Article  CAS  Google Scholar 

  42. Yorikawa C, Shibata H, Waguri S, Hatta K, Horii M, Katoh K, et al. Human CHMP6, a myristoylated ESCRT-III protein, interacts directly with an ESCRT-II component EAP20 and regulates endosomal cargo sorting. Biochem J. 2005;387(Pt 1):17–26.

    Article  CAS  Google Scholar 

  43. Kumar S, Vo AD, Qin F, Li H. Comparative assessment of methods for the fusion transcripts detection from RNA-Seq data. Sci Rep. 2016;6:21597.

    Article  CAS  Google Scholar 

  44. Wang F, Travins J, Delabarre B, Penard-Lacronique V, Schalm S, et al. Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation. Science. 2013;340:622–6.

    Article  CAS  Google Scholar 

  45. Lewis PW, Muller M, Koletsky MS, Cordero F, Lin S, et al. Inhibition of PRC2 activity by gain-of-function H3 mutation found in pediatric glioblastoma. Science. 2013;340:857–61.

    Article  CAS  Google Scholar 

  46. Lehnertz B, Zhang Y, Boivin I, Mayotte N, Tomellini E, et al. H3K27M mutations promote context-dependent transformation in acute myeloid leukemia with RUNX1 alterations. Blood. 2017;130:2204–14.

    Article  CAS  Google Scholar 

  47. Kernytsky A, Wang F, Hansen E, Schalm S, Straley K, et al. IDH2 mutation-induced histone and DNA hypermethylation is progressively reversed by small-molecule inhibition. Blood. 2015;125:296–303.

    Article  CAS  Google Scholar 

  48. Vakoc CR, Kentsis A. Disabling an oncogenic transcription factor by targeting of control kinases. Oncotarget. 2018;9:32276–7.

    Article  Google Scholar 

Download references

Acknowledgements

This paper is dedicated to the memory of Dr. Robert Arceci. This work was supported by the NCI U10 CA98543 (TARGET), U24 CA114766 (COG), U10 CA180886, U10 CA098413, U10 CA180899, P30 CA008748, R01 CA204396, by the Damon Runyon-Richard Lumsden Foundation Clinical Investigator and St. Baldrick’s Foundation Arceci Innovation Awards (to AK), and the Charles E. Trobman Scholarship (to NM). We thank T. Davidsen and P. Gesuwan for their support of the TARGET Data Coordinating Center and Alejandro Gutierrez, Gila Spitzer, and Maria Luisa Sulis for comments on the manuscript.

Author information

Author notes

  1. These authors contributed equally: Nicole A. McNeer, John Philip

Authors and Affiliations

  1. Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Nicole A. McNeer, John Philip, Michael Walsh & Alex Kentsis

  2. New York Genome Center, New York, NY, USA

    Heather Geiger, Minita Shah, Kanika Arora, Anne-Katrin Emde & Nicolas Robine

  3. Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    Rhonda E. Ries & Soheil Meshinchi

  4. Computational and Systems Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Vincent-Philippe Lavallée

  5. Department of Biostatistics, University of Southern California, Los Angeles, CA, USA

    Todd A. Alonzo

  6. Nemours Center for Cancer and Blood Disorders, Nemours/Alfred Dupont Hospital for Children, Wilmington, DE, USA

    E. Anders Kolb

  7. University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA

    Alan S. Gamis

  8. National Cancer Institute, Rockville, MD, USA

    Malcolm Smith, Daniela Se Gerhard & Jaime Guidry-Auvil

  9. Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Alex Kentsis

  10. Department of Pediatrics, Pharmacology, and Physiology & Biophysics, Weill Medical College of Cornell University, New York, NY, USA

    Alex Kentsis

Authors
  1. Nicole A. McNeer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. John Philip
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Heather Geiger
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rhonda E. Ries
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Vincent-Philippe Lavallée
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Michael Walsh
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Minita Shah
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Kanika Arora
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Anne-Katrin Emde
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Nicolas Robine
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Todd A. Alonzo
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. E. Anders Kolb
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Alan S. Gamis
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Malcolm Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Daniela Se Gerhard
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Jaime Guidry-Auvil
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Soheil Meshinchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Alex Kentsis
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Soheil Meshinchi or Alex Kentsis.

Ethics declarations

Conflict of interest

AK is a consultant for Novartis. The other authors declare that they have no conflict of interest.

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

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

McNeer, N.A., Philip, J., Geiger, H. et al. Genetic mechanisms of primary chemotherapy resistance in pediatric acute myeloid leukemia. Leukemia 33, 1934–1943 (2019). https://doi.org/10.1038/s41375-019-0402-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41375-019-0402-3

This article is cited by

Search

Advanced search

Quick links