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
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Rent or buy this article
Prices vary by article type
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
King-Underwood L, Renshaw J, PritchardJones K. Mutations in the Wilms’ tumor gene WT1 in leukemias. Blood. 1996;87:2171–9.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Gabra MM, Salmena L. MicroRNAs and acute myeloid leukemia chemoresistance: a mechanistic overview. Front Oncol. 2017;7:255.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Vakoc CR, Kentsis A. Disabling an oncogenic transcription factor by targeting of control kinases. Oncotarget. 2018;9:32276–7.
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.
Conflict of interest
AK is a consultant for Novartis. The other authors declare that they have no conflict of interest.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
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
This article is cited by
The pediatric leukemia oncoprotein NUP98-KDM5A induces genomic instability that may facilitate malignant transformation
Cell Death & Disease (2023)
Nature Cancer (2023)
Endothelial-derived small extracellular vesicles support B-cell acute lymphoblastic leukemia development
Cellular Oncology (2023)
Prospective Identification of Prognostic Hot-Spot Mutant Gene Signatures for Leukemia: A Computational Study Based on Integrative Analysis of TCGA and cBioPortal Data
Molecular Biotechnology (2023)
Integrated single-cell transcriptome analysis of CD34 + enriched leukemic stem cells revealed intra- and inter-patient transcriptional heterogeneity in pediatric acute myeloid leukemia
Annals of Hematology (2023)