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PMID: 22817890 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

The origin and evolution of mutations in acute myeloid leukemia.

Cell ·Vol. 150 ·No. 2 ·2012-07-20 ·Pages 264-78

Welch JS, Ley TJ, Link DC, Miller CA, Larson DE, Koboldt DC, Wartman LD, Lamprecht TL, Liu F, Xia J, Kandoth C, Fulton RS, McLellan MD, Dooling DJ, Wallis JW, Chen K, Harris CC, Schmidt HK, Kalicki-Veizer JM, Lu C, Zhang Q, Lin L, O'Laughlin MD, McMichael JF, Delehaunty KD, Fulton LA, Magrini VJ, McGrath SD, Demeter RT, Vickery TL, Hundal J, Cook LL, Swift GW, Reed JP, Alldredge PA, Wylie TN, Walker JR, Watson MA, Heath SE, Shannon WD, Varghese N, Nagarajan R, Payton JE, Baty JD, Kulkarni S, Klco JM, Tomasson MH, Westervelt P, Walter MJ, Graubert TA, DiPersio JF, Ding L, Mardis ER, Wilson RK

Abstract

Most mutations in cancer genomes are thought to be acquired after the initiating event, which may cause genomic instability and drive clonal evolution. However, for acute myeloid leukemia (AML), normal karyotypes are common, and genomic instability is unusual. To better understand clonal evolution in AML, we sequenced the genomes of M3-AML samples with a known initiating event (PML-RARA) versus the genomes of normal karyotype M1-AML samples and the exomes of hematopoietic stem/progenitor cells (HSPCs) from healthy people. Collectively, the data suggest that most of the mutations found in AML genomes are actually random events that occurred in HSPCs before they acquired the initiating mutation; the mutational history of that cell is "captured" as the clone expands. In many cases, only one or two additional, cooperating mutations are needed to generate the malignant founding clone. Cells from the founding clone can acquire additional cooperating mutations, yielding subclones that can contribute to disease progression and/or relapse.

MeSH Terms
Adult Aged Clonal Evolution DNA Mutational Analysis Disease Progression Female Genome-Wide Association Study Hematopoietic Stem Cells/metabolism Humans Leukemia, Myeloid, Acute/genetics,physiopathology Male Middle Aged Mutation Oncogene Proteins, Fusion/genetics Recurrence Skin/metabolism Young Adult
Chemicals
Oncogene Proteins, Fusion promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein
Authors & Affiliations
54 authors, click to expand affiliations / ORCID
Welch John S
Department of Medicine, Washington University, St. Louis, MO 63110, USA.
Ley Timothy J
Link Daniel C
Miller Christopher A
Larson David E
Koboldt Daniel C
Wartman Lukas D
Lamprecht Tamara L
Liu Fulu
Xia Jun
Kandoth Cyriac
Fulton Robert S
McLellan Michael D
Dooling David J
Wallis John W
Chen Ken
Harris Christopher C
Schmidt Heather K
Kalicki-Veizer Joelle M
Lu Charles
Zhang Qunyuan
Lin Ling
O'Laughlin Michelle D
McMichael Joshua F
Delehaunty Kim D
Fulton Lucinda A
Magrini Vincent J
McGrath Sean D
Demeter Ryan T
Vickery Tammi L
Hundal Jasreet
Cook Lisa L
Swift Gary W
Reed Jerry P
Alldredge Patricia A
Wylie Todd N
Walker Jason R
Watson Mark A
Heath Sharon E
Shannon William D
Varghese Nobish
Nagarajan Rakesh
Payton Jacqueline E
Baty Jack D
Kulkarni Shashikant
Klco Jeffery M
Tomasson Michael H
Westervelt Peter
Walter Matthew J
Graubert Timothy A
DiPersio John F
Ding Li
Mardis Elaine R
Wilson Richard K
References (69)
69 references, click to expand
  1. Prognosis and therapy when acute promyelocytic leukemia and other "good risk" acute myeloid leukemias occur as a therapy-related myeloid neoplasm.
    Mediterr J Hematol Infect Dis. 2011;3(1):e2011032 PMID: 21869918
  2. Dynamic variation in cycling of hematopoietic stem cells in steady state and inflammation.
    J Exp Med. 2011 Feb 14;208(2):273-84 PMID: 21300914
  3. Acute myeloid leukemia diagnosis in the 21st century.
    Arch Pathol Lab Med. 2010 Oct;134(10):1427-33 PMID: 20923295
  4. Expression profiling of murine acute promyelocytic leukemia cells reveals multiple model-dependent progression signatures.
    Mol Cell Biol. 2004 Dec;24(24):10882-93 PMID: 15572690
  5. Molecular genetics in acute myeloid leukemia.
    Curr Opin Oncol. 2010 Nov;22(6):646-55 PMID: 20805748
  6. SomaticSniper: identification of somatic point mutations in whole genome sequencing data.
    Bioinformatics. 2012 Feb 1;28(3):311-7 PMID: 22155872
  7. Gene mutation patterns and their prognostic impact in a cohort of 1185 patients with acute myeloid leukemia.
    Blood. 2011 Nov 17;118(20):5593-603 PMID: 21881046
  8. Array-based genomic resequencing of human leukemia.
    Oncogene. 2010 Jun 24;29(25):3723-31 PMID: 20400977
  9. Comprehensive analysis of cooperative gene mutations between class I and class II in de novo acute myeloid leukemia.
    Eur J Haematol. 2009 Aug;83(2):90-8 PMID: 19309322
  10. Mutational inactivation of STAG2 causes aneuploidy in human cancer.
    Science. 2011 Aug 19;333(6045):1039-43 PMID: 21852505
  11. Errors in DNA replication as a basis of malignant changes.
    Cancer Res. 1974 Sep;34(9):2311-21 PMID: 4136142
  12. Pretumor progression: clonal evolution of human stem cell populations.
    Am J Pathol. 2004 Apr;164(4):1337-46 PMID: 15039221
  13. Background mutations in parental cells account for most of the genetic heterogeneity of induced pluripotent stem cells.
    Cell Stem Cell. 2012 May 4;10(5):570-82 PMID: 22542160
  14. BreakDancer: an algorithm for high-resolution mapping of genomic structural variation.
    Nat Methods. 2009 Sep;6(9):677-81 PMID: 19668202
  15. Prognostic impact of DNMT3A mutations in patients with intermediate cytogenetic risk profile acute myeloid leukemia.
    Eur J Haematol. 2012 Feb;88(2):128-35 PMID: 21967546
  16. DNA profiling by arrayCGH in acute myeloid leukemia and myelodysplastic syndromes.
    Cytogenet Genome Res. 2007;118(2-4):304-9 PMID: 18000384
  17. The role of FLT3 in haematopoietic malignancies.
    Nat Rev Cancer. 2003 Sep;3(9):650-65 PMID: 12951584
  18. Rara haploinsufficiency modestly influences the phenotype of acute promyelocytic leukemia in mice.
    Blood. 2011 Feb 24;117(8):2460-8 PMID: 21190992
  19. Evidence that hematopoiesis may be a stochastic process in vivo.
    Nat Med. 1996 Feb;2(2):190-7 PMID: 8574964
  20. Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation.
    Nat Biotechnol. 2010 May;28(5):511-5 PMID: 20436464
  21. The replication rate of human hematopoietic stem cells in vivo.
    Blood. 2011 Apr 28;117(17):4460-6 PMID: 21343613
  22. Somatic mutations of JAK1 and JAK3 in acute leukemias and solid cancers.
    Clin Cancer Res. 2008 Jun 15;14(12):3716-21 PMID: 18559588
  23. PML/RARalpha and FLT3-ITD induce an APL-like disease in a mouse model.
    Proc Natl Acad Sci U S A. 2002 Jun 11;99(12):8283-8 PMID: 12060771
  24. Mutagenesis at methylated CpG sequences.
    Curr Top Microbiol Immunol. 2006;301:259-81 PMID: 16570852
  25. CTCF, cohesin, and histone variants: connecting the genome.
    Biochem Cell Biol. 2011 Oct;89(5):505-13 PMID: 21970734
  26. Novel mutation in the PML/RARalpha chimeric gene exhibits dramatically decreased ligand-binding activity and confers acquired resistance to retinoic acid in acute promyelocytic leukemia.
    Exp Hematol. 2001 Jul;29(7):864-72 PMID: 11438209
  27. Analysis of histone 2B-GFP retention reveals slowly cycling hematopoietic stem cells.
    Nat Biotechnol. 2009 Jan;27(1):84-90 PMID: 19060879
  28. High throughput digital quantification of mRNA abundance in primary human acute myeloid leukemia samples.
    J Clin Invest. 2009 Jun;119(6):1714-26 PMID: 19451695
  29. Molecular genetics of human leukemias: new insights into therapy.
    Semin Hematol. 2002 Oct;39(4 Suppl 3):6-11 PMID: 12447846
  30. DNMT3A mutations in acute myeloid leukemia.
    N Engl J Med. 2010 Dec 16;363(25):2424-33 PMID: 21067377
  31. Identification of a novel TP53 cancer susceptibility mutation through whole-genome sequencing of a patient with therapy-related AML.
    JAMA. 2011 Apr 20;305(15):1568-76 PMID: 21505135
  32. Heterogeneous patterns of FLT3 Asp(835) mutations in relapsed de novo acute myeloid leukemia: a comparative analysis of 120 paired diagnostic and relapse bone marrow samples.
    Clin Cancer Res. 2004 Feb 15;10(4):1326-32 PMID: 14977832
  33. Mouse models of acute promyelocytic leukemia.
    Curr Top Microbiol Immunol. 2007;313:3-29 PMID: 17217036
  34. Genetics of therapy-related myelodysplasia and acute myeloid leukemia.
    Leukemia. 2008 Feb;22(2):240-8 PMID: 18200041
  35. Identification of the t(15;17) in AML FAB types other than M3: evaluation of the role of molecular screening for the PML/RARalpha rearrangement in newly diagnosed AML. The Medical Research Council (MRC) Adult Leukaemia Working Party.
    Br J Haematol. 1999 Apr;105(1):198-207 PMID: 10233384
  36. Somatic mutations and germline sequence variants in the expressed tyrosine kinase genes of patients with de novo acute myeloid leukemia.
    Blood. 2008 May 1;111(9):4797-808 PMID: 18270328
  37. Somatically acquired JAK1 mutations in adult acute lymphoblastic leukemia.
    J Exp Med. 2008 Apr 14;205(4):751-8 PMID: 18362173
  38. Acquired copy number alterations in adult acute myeloid leukemia genomes.
    Proc Natl Acad Sci U S A. 2009 Aug 4;106(31):12950-5 PMID: 19651600
  39. Recurrent DNMT3A R882 mutations in Chinese patients with acute myeloid leukemia and myelodysplastic syndrome.
    PLoS One. 2011;6(10):e26906 PMID: 22066015
  40. A two-stage theory of carcinogenesis in relation to the age distribution of human cancer.
    Br J Cancer. 1957 Jun;11(2):161-9 PMID: 13460138
  41. Use of whole-genome sequencing to diagnose a cryptic fusion oncogene.
    JAMA. 2011 Apr 20;305(15):1577-84 PMID: 21505136
  42. A model of APL with FLT3 mutation is responsive to retinoic acid and a receptor tyrosine kinase inhibitor, SU11657.
    Blood. 2003 Apr 15;101(8):3188-97 PMID: 12515727
  43. Clonal architecture of secondary acute myeloid leukemia.
    N Engl J Med. 2012 Mar 22;366(12):1090-8 PMID: 22417201
  44. Alteration of cohesin genes in myeloid diseases.
    Am J Hematol. 2010 Sep;85(9):717-9 PMID: 20687102
  45. Further evidence for a non-random chromosomal abnormality in acute promyelocytic leukemia.
    Int J Cancer. 1977 Dec 15;20(6):869-72 PMID: 271143
  46. Role of promyelocytic leukemia (PML) protein in tumor suppression.
    J Exp Med. 2001 Feb 19;193(4):521-29 PMID: 11181703
  47. Direct mutation analysis by high-throughput sequencing: from germline to low-abundant, somatic variants.
    Mutat Res. 2012 Jan 3;729(1-2):1-15 PMID: 22016070
  48. Management of acute promyelocytic leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet.
    Blood. 2009 Feb 26;113(9):1875-91 PMID: 18812465
  49. Internal tandem duplication of FLT3 (FLT3/ITD) induces increased ROS production, DNA damage, and misrepair: implications for poor prognosis in AML.
    Blood. 2008 Mar 15;111(6):3173-82 PMID: 18192505
  50. WINPEPI updated: computer programs for epidemiologists, and their teaching potential.
    Epidemiol Perspect Innov. 2011 Feb 02;8(1):1 PMID: 21288353
  51. TopHat: discovering splice junctions with RNA-Seq.
    Bioinformatics. 2009 May 1;25(9):1105-11 PMID: 19289445
  52. The clonal evolution of tumor cell populations.
    Science. 1976 Oct 1;194(4260):23-8 PMID: 959840
  53. In vivo kinetics of murine hemopoietic stem cells.
    Blood. 2000 Nov 15;96(10):3399-405 PMID: 11071634
  54. Cooperation between constitutively activated c-Kit signaling and leukemogenic transcription factors in the determination of the leukemic phenotype in murine hematopoietic stem cells.
    Int J Oncol. 2009 Jun;34(6):1521-31 PMID: 19424569
  55. The mutation rate and cancer.
    Proc Natl Acad Sci U S A. 1996 Dec 10;93(25):14800-3 PMID: 8962135
  56. FLT3 mutations at diagnosis and relapse in acute myeloid leukemia: cytogenetic and pathologic correlations, including cuplike blast morphology.
    Arch Pathol Lab Med. 2010 Aug;134(8):1143-51 PMID: 20670134
  57. Evolution of the mutation rate.
    Trends Genet. 2010 Aug;26(8):345-52 PMID: 20594608
  58. Mapping and quantifying mammalian transcriptomes by RNA-Seq.
    Nat Methods. 2008 Jul;5(7):621-8 PMID: 18516045
  59. Recurring mutations found by sequencing an acute myeloid leukemia genome.
    N Engl J Med. 2009 Sep 10;361(11):1058-66 PMID: 19657110
  60. JAK mutations in high-risk childhood acute lymphoblastic leukemia.
    Proc Natl Acad Sci U S A. 2009 Jun 9;106(23):9414-8 PMID: 19470474
  61. Identification of acquired copy number alterations and uniparental disomies in cytogenetically normal acute myeloid leukemia using high-resolution single-nucleotide polymorphism analysis.
    Leukemia. 2010 Feb;24(2):438-49 PMID: 20016533
  62. DNA sequencing of a cytogenetically normal acute myeloid leukaemia genome.
    Nature. 2008 Nov 6;456(7218):66-72 PMID: 18987736
  63. Quantitative trait loci associated with susceptibility to therapy-related acute murine promyelocytic leukemia in hCG-PML/RARA transgenic mice.
    Blood. 2008 Aug 15;112(4):1434-42 PMID: 18552208
  64. Cohesin ties up the genome.
    Curr Opin Cell Biol. 2010 Dec;22(6):781-7 PMID: 20675112
  65. Rearrangement of CRLF2 is associated with mutation of JAK kinases, alteration of IKZF1, Hispanic/Latino ethnicity, and a poor outcome in pediatric B-progenitor acute lymphoblastic leukemia.
    Blood. 2010 Jul 1;115(26):5312-21 PMID: 20139093
  66. Knock-in of an internal tandem duplication mutation into murine FLT3 confers myeloproliferative disease in a mouse model.
    Blood. 2008 Apr 1;111(7):3849-58 PMID: 18245664
  67. Mutations in the E-domain of RAR portion of the PML/RAR chimeric gene may confer clinical resistance to all-trans retinoic acid in acute promyelocytic leukemia.
    Blood. 1998 Jul 15;92(2):374-82 PMID: 9657734
  68. Sequencing a mouse acute promyelocytic leukemia genome reveals genetic events relevant for disease progression.
    J Clin Invest. 2011 Apr;121(4):1445-55 PMID: 21436584
  69. Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing.
    Nature. 2012 Jan 11;481(7382):506-10 PMID: 22237025
Article Info
Journal
Cell
Abbr.
Cell
ISSN
1097-4172
DOI
10.1016/j.cell.2012.06.023
Published
2012-07-20
Pages
264-78
Language
English
Region
United States
NLM ID
0413066
PMCID
PMC3407563
Subset
IM
Grants
NCI NIH HHS · P30 CA91842 · United States
NCI NIH HHS · P01 CA101937 · United States
NCI NIH HHS · R01 CA083962 · United States
NHLBI NIH HHS · K99 HL103975 · United States
NCI NIH HHS · P30 CA091842 · United States
NHGRI NIH HHS · U54 HG003079 · United States
NHLBI NIH HHS · R00 HL103975 · United States
External Links
PubMed source DOI: 10.1016/j.cell.2012.06.023 PMC Full Text View journal details
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