Skip to main content
SpringerLink
Log in

Molecular Malfeasance Mediating Myeloid Malignancies: The Genetics of Acute Myeloid Leukemia

  • Protocol
  • First Online:
Acute Myeloid Leukemia

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1633))

Abstract

A remarkable number of different, but recurrent, structural cytogenetic abnormalities have been observed in AML, and the 2016 WHO AML classification system incorporates numerous distinct entities associated with translocations or inversions, as well as others associated with single gene mutations into a category entitled “AML with recurrent genetic abnormalities.” The AML classification is heavily reliant on cytogenetic and molecular information based on conventional genetic techniques (including karyotype, fluorescence in situ hybridization, reverse transcriptase polymerase chain reaction, single gene sequencing), but large-scale next generation sequencing is now identifying novel mutations. With targeted next generation sequencing panels now clinically available at many centers, detection of mutations, as well as alterations in epigenetic modifiers, is becoming part of the routine diagnostic evaluation of AML and will likely impact future classification schemes.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 119.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 159.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 159.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Bennett JM, Catovsky D, Daniel MT et al (1976) Proposals for the classification of the acute leukaemias. French-American-British (FAB) co-operative group. Br J Haematol 33(4):451–458

    Article  CAS  PubMed  Google Scholar 

  2. Swerdlow S, Campo E, Harris NL et al (2008) WHO classification of tumours of haematopoietic and lymphoid tissues, vol 2, 4th edn. IARC Press, Lyon

    Google Scholar 

  3. Arber DA, Orazi A, Hasserjian R et al (2016) The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 127(20):2391–2405

    Article  CAS  PubMed  Google Scholar 

  4. Foucar K, Anastasi J (2015) Acute myeloid leukemia with recurrent cytogenetic abnormalities. Am J Clin Pathol 144(1):6–18

    Article  CAS  PubMed  Google Scholar 

  5. Degos L (1992) All-trans-retinoic acid treatment and retinoic acid receptor alpha gene rearrangement in acute promyelocytic leukemia: a model for differentiation therapy. Int J Cell Cloning 10(2):63–69

    Article  CAS  PubMed  Google Scholar 

  6. Abla O, Ribeiro RC (2014) How I treat children and adolescents with acute promyelocytic leukaemia. Br J Haematol 164(1):24–38

    Article  CAS  PubMed  Google Scholar 

  7. Molica M, Breccia M (2015) FLT3-ITD in acute promyelocytic leukemia: clinical distinct profile but still controversial prognosis. Leuk Res 39(4):397–399

    Article  PubMed  Google Scholar 

  8. Adams J, Nassiri M (2015) Acute Promyelocytic leukemia: a review and discussion of variant translocations. Arch Pathol Lab Med 139(10):1308–1313

    Article  PubMed  Google Scholar 

  9. Brunel V, Lafage-Pochitaloff M, Alcalay M, Pelicci PG, Birg F (1996) Variant and masked translocations in acute promyelocytic leukemia. Leuk Lymphoma 22(3–4):221–228

    Article  CAS  PubMed  Google Scholar 

  10. Jansen JH, Lowenberg B (2001) Acute promyelocytic leukemia with a PLZF-RARalpha fusion protein. Semin Hematol 38(1):37–41

    Article  CAS  PubMed  Google Scholar 

  11. Guidez F, Parks S, Wong H et al (2007) RARalpha-PLZF overcomes PLZF-mediated repression of CRABPI, contributing to retinoid resistance in t(11;17) acute promyelocytic leukemia. Proc Natl Acad Sci U S A 104(47):18694–18699

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Redner RL (2002) Variations on a theme: the alternate translocations in APL. Leukemia 16(10):1927–1932

    Article  CAS  PubMed  Google Scholar 

  13. Rossi V, Levati L, Biondi A (2006) Diagnosis and monitoring of PML-RARA-positive acute promyelocytic leukemia by qualitative RT-PCR. Methods Mol Med 125:115–126

    CAS  PubMed  Google Scholar 

  14. Sinha C, Cunningham LC, Liu PP (2015) Core binding factor acute myeloid leukemia: new prognostic categories and therapeutic opportunities. Semin Hematol 52(3):215–222

    Article  PubMed  PubMed Central  Google Scholar 

  15. Grimwade D, Hills RK, Moorman AV et al (2010) Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials. Blood 116:354–365

    Article  CAS  PubMed  Google Scholar 

  16. Wong KF, Kwong YL (1999) Trisomy 22 in acute myeloid leukemia: a marker for myeloid leukemia with monocytic features and cytogenetically cryptic inversion 16. Cancer Genet Cytogenet 109(2):131–133

    Article  CAS  PubMed  Google Scholar 

  17. Costello R, Sainty D, Lecine P et al (1997) Detection of CBFbeta/MYH11 fusion transcripts in acute myeloid leukemia: heterogeneity of cytological and molecular characteristics. Leukemia 11(5):644–650

    Article  CAS  PubMed  Google Scholar 

  18. Claxton D, Xie QS, Patel S, Deisseroth AB, Kornblau S (1996) The gene product of CBFB-MYH11. Leukemia 10(9):1479–1485

    CAS  PubMed  Google Scholar 

  19. Paschka P, Du J, Schlenk RF et al (2013) Secondary genetic lesions in acute myeloid leukemia with inv(16) or t(16;16): a study of the German-Austrian AML study group (AMLSG). Blood 121(1):170–177

    Article  CAS  PubMed  Google Scholar 

  20. Paschka P, Marcucci G, Ruppert AS et al (2006) Adverse prognostic significance of KIT mutations in adult acute myeloid leukemia with inv(16) and t(8;21): a cancer and leukemia group B study. J Clin Oncol 24(24):3904–3911

    Article  CAS  PubMed  Google Scholar 

  21. Schoch C, Schnittger S, Klaus M et al (2003) AML with 11q23//MLL abnormalities as defined by the WHO classification: incidence, partner chromosomes, FAB subtype, age distribution, and prognostic impact in an unselected series of 1897 cytogenetically analyzed AML cases. Blood 102:2395–2402

    Article  CAS  PubMed  Google Scholar 

  22. Meyer C, Hofmann J, Burmeister T et al (2013) The MLL recombinome of acute leukemias in 2013. Leukemia 27(11):2165–2176

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Balgobind BV, Raimondi SC, Harbott J et al (2009) Novel prognostic subgroups in childhood 11q23/MLL-rearranged acute myeloid leukemia: results of an international retrospective study. Blood 114(12):2489–2496

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Fianchi L, Pagano L, Piciocchi A et al (2015) Characteristics and outcome of therapy-related myeloid neoplasms: report from the Italian network on secondary leukemias. Am J Hematol 90(5):E80–E85

    Article  CAS  PubMed  Google Scholar 

  25. Krivtsov AV, Armstrong SA (2007) MLL translocations, histone modifications and leukaemia stem-cell development. Nat Rev Cancer 7(11):823–833

    Article  CAS  PubMed  Google Scholar 

  26. Chen CW, Koche RP, Sinha AU et al (2015) DOT1L inhibits SIRT1-mediated epigenetic silencing to maintain leukemic gene expression in MLL-rearranged leukemia. Nat Med 21(4):335–343

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Zhou J, Wu J, Li B et al (2014) PU.1 is essential for MLL leukemia partially via crosstalk with the MEIS/HOX pathway. Leukemia 28(7):1436–1448

    Article  CAS  PubMed  Google Scholar 

  28. Aikawa Y, Yamagata K, Katsumoto T et al (2015) Essential role of PU.1 in maintenance of mixed lineage leukemia-associated leukemic stem cells. Cancer Sci 106(3):227–236

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Emerenciano M, Meyer C, Mansur MB, Marschalek R, Pombo-de-Oliveira MS (2013) The distribution of MLL breakpoints correlates with outcome in infant acute leukaemia. Br J Haematol 161(2):224–236

    Article  PubMed  Google Scholar 

  30. Tarlock K, Alonzo TA, Moraleda PP et al (2014) Acute myeloid leukaemia (AML) with t(6;9)(p23;q34) is associated with poor outcome in childhood AML regardless of FLT3-ITD status: a report from the Children’s oncology group. Br J Haematol 166(2):254–259

    Article  PubMed  PubMed Central  Google Scholar 

  31. Ageberg M, Drott K, Olofsson T, Gullberg U, Lindmark A (2008) Identification of a novel and myeloid specific role of the leukemia-associated fusion protein DEK-NUP214 leading to increased protein synthesis. Genes Chromosomes Cancer 47(4):276–287

    Article  CAS  PubMed  Google Scholar 

  32. von Lindern M, Breems D, van Baal S, Adriaansen H, Grosveld G (1992) Characterization of the translocation breakpoint sequences of two DEK-CAN fusion genes present in t(6;9) acute myeloid leukemia and a SET-CAN fusion gene found in a case of acute undifferentiated leukemia. Genes Chromosomes Cancer 5(3):227–234

    Article  Google Scholar 

  33. Lugthart S, Groschel S, Beverloo HB et al (2010) Clinical, molecular, and prognostic significance of WHO type inv(3)(q21q26.2)/t(3;3)(q21;q26.2) and various other 3q abnormalities in acute myeloid leukemia. J Clin Oncol 28(24):3890–3898

    Article  PubMed  Google Scholar 

  34. Yamazaki H, Suzuki M, Otsuki A et al (2014) A remote GATA2 hematopoietic enhancer drives leukemogenesis in inv(3)(q21;q26) by activating EVI1 expression. Cancer Cell 25(4):415–427

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Shearer BM, Sukov WR, Flynn HC, Knudson RA, Ketterling RP (2010) Development of a dual-color, double fusion FISH assay to detect RPN1/EVI1 gene fusion associated with inv(3), t(3;3), and ins(3;3) in patients with myelodysplasia and acute myeloid leukemia. Am J Hematol 85(8):569–574

    Article  PubMed  Google Scholar 

  36. Lion T, Haas OA (1993) Acute megakaryocytic leukemia with the t(1;22)(p13;q13). Leuk Lymphoma 11(1–2):15–20

    Article  CAS  PubMed  Google Scholar 

  37. Carroll A, Civin C, Schneider N et al (1991) The t(1;22) (p13;q13) is nonrandom and restricted to infants with acute megakaryoblastic leukemia: a pediatric oncology group study. Blood 78(3):748–752

    CAS  PubMed  Google Scholar 

  38. Inaba H, Zhou Y, Abla O et al (2015) Heterogeneous cytogenetic subgroups and outcomes in childhood acute megakaryoblastic leukemia: a retrospective international study. Blood 126(13):1575–1584

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Mercher T, Raffel GD, Moore SA et al (2009) The OTT-MAL fusion oncogene activates RBPJ-mediated transcription and induces acute megakaryoblastic leukemia in a knockin mouse model. J Clin Invest 119(4):852–864

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Soupir CP, Vergilio JA, Dal Cin P et al (2007) Philadelphia chromosome-positive acute myeloid leukemia: a rare aggressive leukemia with clinicopathologic features distinct from chronic myeloid leukemia in myeloid blast crisis. Am J Clin Pathol 127(4):642–650

    Article  PubMed  Google Scholar 

  41. Nacheva EP, Grace CD, Brazma D et al (2013) Does BCR/ABL1 positive acute myeloid leukaemia exist? Br J Haematol 161(4):541–550

    Article  CAS  PubMed  Google Scholar 

  42. Konoplev S, Yin CC, Kornblau SM et al (2013) Molecular characterization of de novo Philadelphia chromosome-positive acute myeloid leukemia. Leuk Lymphoma 54(1):138–144

    Article  CAS  PubMed  Google Scholar 

  43. Moon JH, Lee YJ, Seo SK et al (2015) Outcomes of allogeneic hematopoietic cell transplantation in acute myeloid leukemia patients with monosomal karyotypes. Acta Haematol 133(4):327–335

    Article  PubMed  Google Scholar 

  44. Weinberg OK, Ohgami RS, Ma L et al (2014) Acute myeloid leukemia with monosomal karyotype: morphologic, immunophenotypic, and molecular findings. Am J Clin Pathol 142(2):190–195

    Article  PubMed  Google Scholar 

  45. Murati A, Brecqueville M, Devillier R et al (2012) Myeloid malignancies: mutations, models and management. BMC Cancer 12:304

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Meyer SC, Levine RL (2014) Translational implications of somatic genomics in acute myeloid leukaemia. Lancet Oncol 15(9):e382–ee94

    Article  CAS  PubMed  Google Scholar 

  47. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia (2013) N Engl J Med 368(22):2059–2074

    Article  Google Scholar 

  48. Ohgami RS, Ma L, Merker JD et al (2015) Next-generation sequencing of acute myeloid leukemia identifies the significance of TP53, U2AF1, ASXL1, and TET2 mutations. Mod Pathol 28(5):706–714

    Article  CAS  PubMed  Google Scholar 

  49. Colombo E, Marine JC, Danovi D, Falini B, Pelicci PG (2002) Nucleophosmin regulates the stability and transcriptional activity of p53. Nat Cell Biol 4(7):529–533

    Article  CAS  PubMed  Google Scholar 

  50. Boissel N, Renneville A, Biggio V et al (2005) Prevalence, clinical profile, and prognosis of NPM mutations in AML with normal karyotype. Blood 106(10):3618–3620

    Article  CAS  PubMed  Google Scholar 

  51. Thiede C, Koch S, Creutzig E et al (2006) Prevalence and prognostic impact of NPM1 mutations in 1485 adult patients with acute myeloid leukemia (AML). Blood 107(10):4011–4020

    Article  CAS  PubMed  Google Scholar 

  52. Diaz-Beya M, Rozman M, Pratcorona M et al (2010) The prognostic value of multilineage dysplasia in de novo acute myeloid leukemia patients with intermediate-risk cytogenetics is dependent on NPM1 mutational status. Blood 116(26):6147–6148

    Article  CAS  PubMed  Google Scholar 

  53. Stirewalt DL, Radich JP (2003) The role of FLT3 in haematopoietic malignancies. Nat Rev Cancer 3(9):650–665

    Article  CAS  PubMed  Google Scholar 

  54. Thiede C, Steudel C, Mohr B et al (2002) Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood 99(12):4326–4335

    Article  CAS  PubMed  Google Scholar 

  55. Grunwald MR, Levis MJ (2015) FLT3 tyrosine kinase inhibition as a paradigm for targeted drug development in acute myeloid leukemia. Semin Hematol 52(3):193–199

    Article  CAS  PubMed  Google Scholar 

  56. Pabst T, Mueller BU, Zhang P et al (2001) Dominant-negative mutations of CEBPA, encoding CCAAT/enhancer binding protein-alpha (C/EBPalpha), in acute myeloid leukemia. Nat Genet 27(3):263–270

    Article  CAS  PubMed  Google Scholar 

  57. Green CL, Koo KK, Hills RK et al (2010) Prognostic significance of CEBPA mutations in a large cohort of younger adult patients with acute myeloid leukemia: impact of double CEBPA mutations and the interaction with FLT3 and NPM1 mutations. J Clin Oncol 28(16):2739–2747

    Article  CAS  PubMed  Google Scholar 

  58. Bacher U, Schnittger S, Macijewski K et al (2012) Multilineage dysplasia does not influence prognosis in CEBPA-mutated AML, supporting the WHO proposal to classify these patients as a unique entity. Blood 119(20):4719–4722

    Article  CAS  PubMed  Google Scholar 

  59. Gaidzik VI, Bullinger L, Schlenk RF et al (2011) RUNX1 mutations in acute myeloid leukemia: results from a comprehensive genetic and clinical analysis from the AML study group. J Clin Oncol 29(10):1364–1372

    Article  PubMed  Google Scholar 

  60. Dohner K, Tobis K, Ulrich R et al (2002) Prognostic significance of partial tandem duplications of the MLL gene in adult patients 16 to 60 years old with acute myeloid leukemia and normal cytogenetics: a study of the acute myeloid leukemia study group Ulm. J Clin Oncol 20(15):3254–3261

    Article  PubMed  Google Scholar 

  61. DiNardo CD, Bannon SA, Routbort M et al (2016) Evaluation of patients and families with concern for predispositions to hematologic malignancies within the hereditary hematologic malignancy clinic (HHMC). Clin Lymphoma Myeloma Leuk 16(7):417–428

    Article  PubMed  PubMed Central  Google Scholar 

  62. Wertheim GB, Smith C, Luskin M et al (2015) Validation of DNA methylation to predict outcome in acute myeloid leukemia by use of xMELP. Clin Chem 61(1):249–258

    Article  CAS  PubMed  Google Scholar 

  63. Figueroa ME, Lugthart S, Li Y et al (2010) DNA methylation signatures identify biologically distinct subtypes in acute myeloid leukemia. Cancer Cell 17(1):13–27

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Ley TJ, Ding L, Walter MJ et al (2010) DNMT3A mutations in acute myeloid leukemia. N Engl J Med 363:2424–2433

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Yan XJ, Xu J, Gu ZH et al (2011) Exome sequencing identifies somatic mutations of DNA methyltransferase gene DNMT3A in acute monocytic leukemia. Nat Genet 43(4):309–315

    Article  CAS  PubMed  Google Scholar 

  66. Bhatnagar B, Eisfeld AK, Nicolet D et al (2016) Persistence of DNMT3A R882 mutations during remission does not adversely affect outcomes of patients with acute myeloid leukaemia. Br J Haematol 175(2):226–236

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Lindsley RC, Mar BG, Mazzola E et al (2015) Acute myeloid leukemia ontogeny is defined by distinct somatic mutations. Blood 125(9):1367–1376

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Hematopathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA

    Rebecca L. King

  2. Division of Hematopathology, Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, 7103 Founders Pavilion, 3400 Spruce Street, Philadelphia, PA, USA

    Adam Bagg

Authors
  1. Rebecca L. King
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Adam Bagg
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Adam Bagg .

Editor information

Editors and Affiliations

  1. Thomas Jefferson University, Sidney Kimmel Cancer Center, Philadelphia, Pennsylvania, USA

    Paolo Fortina

  2. Department of Pathology, Anatomy and Cell Biology, Sidney Kimmel Medical College Thomas Jefferson University, Philadelphia, Pennsylvania, USA

    Eric Londin

  3. Department of Pathology, UT Southwestern Medical Center and Children’s Medical Center, Dallas, Texas, USA

    Jason Y. Park

  4. Department of Pathology and Laboratory Medicine, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania, USA

    Larry J. Kricka

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer Science+Business Media LLC

About this protocol

Cite this protocol

King, R.L., Bagg, A. (2017). Molecular Malfeasance Mediating Myeloid Malignancies: The Genetics of Acute Myeloid Leukemia. In: Fortina, P., Londin, E., Park, J., Kricka, L. (eds) Acute Myeloid Leukemia. Methods in Molecular Biology, vol 1633. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-7142-8_1

Download citation

  • DOI: https://doi.org/10.1007/978-1-4939-7142-8_1

  • Published:

  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-4939-7140-4

  • Online ISBN: 978-1-4939-7142-8

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation