Official reprint from UpToDate®
www.uptodate.com ©2016 UpToDate®

Pathogenesis of acute myeloid leukemia

Wendy Stock, MD
Michael J Thirman, MD
Section Editor
Richard A Larson, MD
Deputy Editor
Alan G Rosmarin, MD


Acute myeloid leukemia (AML) develops as the consequence of a series of genetic changes in a hematopoietic precursor cell. These changes alter normal hematopoietic growth and differentiation, resulting in an accumulation of large numbers of abnormal, immature myeloid cells in the bone marrow and peripheral blood. These cells are capable of dividing and proliferating, but cannot differentiate into mature hematopoietic cells (ie, neutrophils).

This topic will review the cell of origin and the multistep and multi-causal pathogenesis of AML. More detailed descriptions of the molecular basis of AML and the genetic abnormalities seen in AML are presented separately, as is a discussion of familial acute leukemia and myelodysplastic syndromes. (See "Molecular genetics of acute myeloid leukemia" and "Cytogenetics in acute myeloid leukemia" and "Prognosis of acute myeloid leukemia" and "Familial acute leukemia and myelodysplastic syndromes".)


Normal counterpart — Leukemia is a heterogenous group of diseases characterized by clonal cells that exhibit maturation defects that correspond to stages in hematopoietic differentiation. Hematopoietic stem cells are multipotent and have the capacity to differentiate into the cells of all 10 blood lineages — erythrocytes, platelets, neutrophils, eosinophils, basophils, monocytes, T and B lymphocytes, natural killer cells, and dendritic cells. In order to sustain hematopoiesis, stem cells are part of a developmental hierarchy capable of three basic functions:

Maintenance in a non-cycling state (ie, not actively progressing through the cell cycle)

Self-renewal, allowing production of additional stem cells


Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Sep 2016. | This topic last updated: Mar 16, 2016.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2016 UpToDate, Inc.
  1. Godin IE, Garcia-Porrero JA, Coutinho A, et al. Para-aortic splanchnopleura from early mouse embryos contains B1a cell progenitors. Nature 1993; 364:67.
  2. Botnick LE, Hannon EC, Hellman S. Nature of the hemopoietic stem cell compartment and its proliferative potential. Blood Cells 1979; 5:195.
  3. Orkin SH. Transcription factors and hematopoietic development. J Biol Chem 1995; 270:4955.
  4. Tenen DG, Hromas R, Licht JD, Zhang DE. Transcription factors, normal myeloid development, and leukemia. Blood 1997; 90:489.
  5. Rabbitts TH. Chromosomal translocations in human cancer. Nature 1994; 372:143.
  6. Genovese G, Kähler AK, Handsaker RE, et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N Engl J Med 2014; 371:2477.
  7. Jaiswal S, Fontanillas P, Flannick J, et al. Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med 2014; 371:2488.
  8. Xie M, Lu C, Wang J, et al. Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nat Med 2014; 20:1472.
  9. Fialkow PJ, Singer JW, Adamson JW, et al. Acute nonlymphocytic leukemia: expression in cells restricted to granulocytic and monocytic differentiation. N Engl J Med 1979; 301:1.
  10. Fialkow PJ, Singer JW, Adamson JW, et al. Acute nonlymphocytic leukemia: heterogeneity of stem cell origin. Blood 1981; 57:1068.
  11. Ferraris AM, Canepa L, Mareni C, et al. Reexpression of normal stem cells in erythroleukemia during remission. Blood 1983; 62:177.
  12. Fearon ER, Burke PJ, Schiffer CA, et al. Differentiation of leukemia cells to polymorphonuclear leukocytes in patients with acute nonlymphocytic leukemia. N Engl J Med 1986; 315:15.
  13. Keinänen M, Griffin JD, Bloomfield CD, et al. Clonal chromosomal abnormalities showing multiple-cell-lineage involvement in acute myeloid leukemia. N Engl J Med 1988; 318:1153.
  14. van Lom K, Hagemeijer A, Smit EM, Löwenberg B. In situ hybridization on May-Grünwald Giemsa-stained bone marrow and blood smears of patients with hematologic disorders allows detection of cell-lineage-specific cytogenetic abnormalities. Blood 1993; 82:884.
  15. Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 1997; 3:730.
  16. Kelly PN, Dakic A, Adams JM, et al. Tumor growth need not be driven by rare cancer stem cells. Science 2007; 317:337.
  17. Turhan AG, Lemoine FM, Debert C, et al. Highly purified primitive hematopoietic stem cells are PML-RARA negative and generate nonclonal progenitors in acute promyelocytic leukemia. Blood 1995; 85:2154.
  18. McCulloch EA. Stem cells in normal and leukemic hemopoiesis (Henry Stratton Lecture, 1982). Blood 1983; 62:1.
  19. Bonnet D. Normal and leukaemic stem cells. Br J Haematol 2005; 130:469.
  20. Civin CI, Strauss LC, Brovall C, et al. Antigenic analysis of hematopoiesis. III. A hematopoietic progenitor cell surface antigen defined by a monoclonal antibody raised against KG-1a cells. J Immunol 1984; 133:157.
  21. Terstappen LW, Huang S, Safford M, et al. Sequential generations of hematopoietic colonies derived from single nonlineage-committed CD34+CD38- progenitor cells. Blood 1991; 77:1218.
  22. Stubbs MC, Armstrong SA. Therapeutic implications of leukemia stem cell development. Clin Cancer Res 2007; 13:3439.
  23. Huang S, Terstappen LW. Formation of haematopoietic microenvironment and haematopoietic stem cells from single human bone marrow stem cells. Nature 1992; 360:745.
  24. Mehrotra B, George TI, Kavanau K, et al. Cytogenetically aberrant cells in the stem cell compartment (CD34+lin-) in acute myeloid leukemia. Blood 1995; 86:1139.
  25. Haase D, Feuring-Buske M, Könemann S, et al. Evidence for malignant transformation in acute myeloid leukemia at the level of early hematopoietic stem cells by cytogenetic analysis of CD34+ subpopulations. Blood 1995; 86:2906.
  26. Levis M, Murphy KM, Pham R, et al. Internal tandem duplications of the FLT3 gene are present in leukemia stem cells. Blood 2005; 106:673.
  27. Nilsson L, Astrand-Grundström I, Arvidsson I, et al. Isolation and characterization of hematopoietic progenitor/stem cells in 5q-deleted myelodysplastic syndromes: evidence for involvement at the hematopoietic stem cell level. Blood 2000; 96:2012.
  28. Miura I, Kobayashi Y, Takahashi N, et al. Involvement of natural killer cells in patients with myelodysplastic syndrome carrying monosomy 7 revealed by the application of fluorescence in situ hybridization to cells collected by means of fluorescence-activated cell sorting. Br J Haematol 2000; 110:876.
  29. Lapidot T, Sirard C, Vormoor J, et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 1994; 367:645.
  30. Sutherland H, Blair A, Vercauteren S, Zapf R. Detection and clinical significance of human acute myeloid leukaemia progenitors capable of long-term proliferation in vitro. Br J Haematol 2001; 114:296.
  31. Bhatia M, Wang JC, Kapp U, et al. Purification of primitive human hematopoietic cells capable of repopulating immune-deficient mice. Proc Natl Acad Sci U S A 1997; 94:5320.
  32. Cox CV, Evely RS, Oakhill A, et al. Characterization of acute lymphoblastic leukemia progenitor cells. Blood 2004; 104:2919.
  33. Mulloy JC, Cammenga J, MacKenzie KL, et al. The AML1-ETO fusion protein promotes the expansion of human hematopoietic stem cells. Blood 2002; 99:15.
  34. Tonks A, Pearn L, Tonks AJ, et al. The AML1-ETO fusion gene promotes extensive self-renewal of human primary erythroid cells. Blood 2003; 101:624.
  35. Fialkow PJ, Singer JW, Raskind WH, et al. Clonal development, stem-cell differentiation, and clinical remissions in acute nonlymphocytic leukemia. N Engl J Med 1987; 317:468.
  36. Konopleva M, Konoplev S, Hu W, et al. Stromal cells prevent apoptosis of AML cells by up-regulation of anti-apoptotic proteins. Leukemia 2002; 16:1713.
  37. Colmone A, Amorim M, Pontier AL, et al. Leukemic cells create bone marrow niches that disrupt the behavior of normal hematopoietic progenitor cells. Science 2008; 322:1861.
  38. Lane SW, Scadden DT, Gilliland DG. The leukemic stem cell niche: current concepts and therapeutic opportunities. Blood 2009; 114:1150.
  39. Ustun C, Miller JS, Munn DH, et al. Regulatory T cells in acute myelogenous leukemia: is it time for immunomodulation? Blood 2011; 118:5084.
  40. Zeng Z, Shi YX, Samudio IJ, et al. Targeting the leukemia microenvironment by CXCR4 inhibition overcomes resistance to kinase inhibitors and chemotherapy in AML. Blood 2009; 113:6215.
  41. Nervi B, Ramirez P, Rettig MP, et al. Chemosensitization of acute myeloid leukemia (AML) following mobilization by the CXCR4 antagonist AMD3100. Blood 2009; 113:6206.
  42. Cheng H, Hao S, Liu Y, et al. Leukemic marrow infiltration reveals a novel role for Egr3 as a potent inhibitor of normal hematopoietic stem cell proliferation. Blood 2015; 126:1302.
  43. Miraki-Moud F, Anjos-Afonso F, Hodby KA, et al. Acute myeloid leukemia does not deplete normal hematopoietic stem cells but induces cytopenias by impeding their differentiation. Proc Natl Acad Sci U S A 2013; 110:13576.
  44. Jacobs A. Leukaemia Research Fund annual guest lecture 1990. Genetics lesions in preleukaemia. Leukemia 1991; 5:277.
  45. Ley TJ, Mardis ER, Ding L, et al. DNA sequencing of a cytogenetically normal acute myeloid leukaemia genome. Nature 2008; 456:66.
  46. Mardis ER, Ding L, Dooling DJ, et al. Recurring mutations found by sequencing an acute myeloid leukemia genome. N Engl J Med 2009; 361:1058.
  47. Radtke I, Mullighan CG, Ishii M, et al. Genomic analysis reveals few genetic alterations in pediatric acute myeloid leukemia. Proc Natl Acad Sci U S A 2009; 106:12944.
  48. Walter MJ, Payton JE, Ries RE, et al. Acquired copy number alterations in adult acute myeloid leukemia genomes. Proc Natl Acad Sci U S A 2009; 106:12950.
  49. Reilly JT. Pathogenesis of acute myeloid leukaemia and inv(16)(p13;q22): a paradigm for understanding leukaemogenesis? Br J Haematol 2005; 128:18.
  50. Bachas C, Schuurhuis GJ, Hollink IH, et al. High-frequency type I/II mutational shifts between diagnosis and relapse are associated with outcome in pediatric AML: implications for personalized medicine. Blood 2010; 116:2752.
  51. Kurzrock R, Gutterman JU, Talpaz M. The molecular genetics of Philadelphia chromosome-positive leukemias. N Engl J Med 1988; 319:990.
  52. Daley GQ, Van Etten RA, Baltimore D. Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome. Science 1990; 247:824.
  53. Rubin CM, Larson RA, Anastasi J, et al. t(3;21)(q26;q22): a recurring chromosomal abnormality in therapy-related myelodysplastic syndrome and acute myeloid leukemia. Blood 1990; 76:2594.
  54. Feinstein E, Cimino G, Gale RP, et al. p53 in chronic myelogenous leukemia in acute phase. Proc Natl Acad Sci U S A 1991; 88:6293.
  55. Fialkow PJ, Janssen JW, Bartram CR. Clonal remissions in acute nonlymphocytic leukemia: evidence for a multistep pathogenesis of the malignancy. Blood 1991; 77:1415.
  56. Bartram CR, Ludwig WD, Hiddemann W, et al. Acute myeloid leukemia: analysis of ras gene mutations and clonality defined by polymorphic X-linked loci. Leukemia 1989; 3:247.
  57. Busque L, Gilliland DG. Clonal evolution in acute myeloid leukemia. Blood 1993; 82:337.
  58. Gale RE, Mein CA, Linch DC. Quantification of X-chromosome inactivation patterns in haematological samples using the DNA PCR-based HUMARA assay. Leukemia 1996; 10:362.
  59. Busque L, Mio R, Mattioli J, et al. Nonrandom X-inactivation patterns in normal females: lyonization ratios vary with age. Blood 1996; 88:59.
  60. Jowitt SN, Liu Yin JA, Saunders MJ, Lucas GS. Clonal remissions in acute myeloid leukaemia are commonly associated with features of trilineage myelodysplasia during remission. Br J Haematol 1993; 85:698.
  61. Jinnai I, Nagai K, Yoshida S, et al. Incidence and characteristics of clonal hematopoiesis in remission of acute myeloid leukemia in relation to morphological dysplasia. Leukemia 1995; 9:1756.
  62. Ding L, Ley TJ, Larson DE, et al. Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing. Nature 2012; 481:506.
  63. Parkin B, Ouillette P, Li Y, et al. Clonal evolution and devolution after chemotherapy in adult acute myelogenous leukemia. Blood 2013; 121:369.
  64. Bochtler T, Stölzel F, Heilig CE, et al. Clonal heterogeneity as detected by metaphase karyotyping is an indicator of poor prognosis in acute myeloid leukemia. J Clin Oncol 2013; 31:3898.
  65. Cancer Genome Atlas Research Network. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med 2013; 368:2059.
  66. Walter MJ, Shen D, Ding L, et al. Clonal architecture of secondary acute myeloid leukemia. N Engl J Med 2012; 366:1090.
  67. Yuan Y, Zhou L, Miyamoto T, et al. AML1-ETO expression is directly involved in the development of acute myeloid leukemia in the presence of additional mutations. Proc Natl Acad Sci U S A 2001; 98:10398.
  68. Nishida S, Hosen N, Shirakata T, et al. AML1-ETO rapidly induces acute myeloblastic leukemia in cooperation with the Wilms tumor gene, WT1. Blood 2006; 107:3303.
  69. Nucifora G, Larson RA, Rowley JD. Persistence of the 8;21 translocation in patients with acute myeloid leukemia type M2 in long-term remission. Blood 1993; 82:712.
  70. Jurlander J, Caligiuri MA, Ruutu T, et al. Persistence of the AML1/ETO fusion transcript in patients treated with allogeneic bone marrow transplantation for t(8;21) leukemia. Blood 1996; 88:2183.
  71. Wiemels JL, Xiao Z, Buffler PA, et al. In utero origin of t(8;21) AML1-ETO translocations in childhood acute myeloid leukemia. Blood 2002; 99:3801.
  72. Hjalgrim LL, Madsen HO, Melbye M, et al. Presence of clone-specific markers at birth in children with acute lymphoblastic leukaemia. Br J Cancer 2002; 87:994.
  73. Kuchenbauer F, Schnittger S, Look T, et al. Identification of additional cytogenetic and molecular genetic abnormalities in acute myeloid leukaemia with t(8;21)/AML1-ETO. Br J Haematol 2006; 134:616.
  74. Krejci O, Wunderlich M, Geiger H, et al. p53 signaling in response to increased DNA damage sensitizes AML1-ETO cells to stress-induced death. Blood 2008; 111:2190.
  75. Yan M, Kanbe E, Peterson LF, et al. A previously unidentified alternatively spliced isoform of t(8;21) transcript promotes leukemogenesis. Nat Med 2006; 12:945.
  76. Pagana L, Pulsoni A, Tosti ME, et al. Clinical and biological features of acute myeloid leukaemia occurring as second malignancy: GIMEMA archive of adult acute leukaemia. Br J Haematol 2001; 112:109.
  77. Levine EG, Bloomfield CD. Leukemias and myelodysplastic syndromes secondary to drug, radiation, and environmental exposure. Semin Oncol 1992; 19:47.
  78. DeCillis A, Anderson S, Wickerham DL, et al. Acute myeloid leukemia in NSABP-25. Proc ASCO 1995; 14:98.
  79. Miller JS, Arthur DC, Litz CE, et al. Myelodysplastic syndrome after autologous bone marrow transplantation: an additional late complication of curative cancer therapy. Blood 1994; 83:3780.
  80. Stone RM, Neuberg D, Soiffer R, et al. Myelodysplastic syndrome as a late complication following autologous bone marrow transplantation for non-Hodgkin's lymphoma. J Clin Oncol 1994; 12:2535.
  81. Darrington DL, Vose JM, Anderson JR, et al. Incidence and characterization of secondary myelodysplastic syndrome and acute myelogenous leukemia following high-dose chemoradiotherapy and autologous stem-cell transplantation for lymphoid malignancies. J Clin Oncol 1994; 12:2527.
  82. Seedhouse C, Russell N. Advances in the understanding of susceptibility to treatment-related acute myeloid leukaemia. Br J Haematol 2007; 137:513.
  83. Guillem V, Tormo M. Influence of DNA damage and repair upon the risk of treatment related leukemia. Leuk Lymphoma 2008; 49:204.
  84. Le Beau MM, Albain KS, Larson RA, et al. Clinical and cytogenetic correlations in 63 patients with therapy-related myelodysplastic syndromes and acute nonlymphocytic leukemia: further evidence for characteristic abnormalities of chromosomes no. 5 and 7. J Clin Oncol 1986; 4:325.
  85. Thirman MJ, Gill HJ, Burnett RC, et al. Rearrangement of the MLL gene in acute lymphoblastic and acute myeloid leukemias with 11q23 chromosomal translocations. N Engl J Med 1993; 329:909.
  86. Albain KS, Le Beau MM, Ullirsch R, Schumacher H. Implication of prior treatment with drug combinations including inhibitors of topoisomerase II in therapy-related monocytic leukemia with a 9;11 translocation. Genes Chromosomes Cancer 1990; 2:53.
  87. Pedersen-Bjergaard J, Philip P. Two different classes of therapy-related and de-novo acute myeloid leukemia? Cancer Genet Cytogenet 1991; 55:119.
  88. Super HJ, McCabe NR, Thirman MJ, et al. Rearrangements of the MLL gene in therapy-related acute myeloid leukemia in patients previously treated with agents targeting DNA-topoisomerase II. Blood 1993; 82:3705.
  89. Chakraborty S, Sun CL, Francisco L, et al. Accelerated telomere shortening precedes development of therapy-related myelodysplasia or acute myelogenous leukemia after autologous transplantation for lymphoma. J Clin Oncol 2009; 27:791.
  90. Calado RT, Regal JA, Hills M, et al. Constitutional hypomorphic telomerase mutations in patients with acute myeloid leukemia. Proc Natl Acad Sci U S A 2009; 106:1187.
  91. Allan JM, Wild CP, Rollinson S, et al. Polymorphism in glutathione S-transferase P1 is associated with susceptibility to chemotherapy-induced leukemia. Proc Natl Acad Sci U S A 2001; 98:11592.
  92. Bolufer P, Collado M, Barragan E, et al. Profile of polymorphisms of drug-metabolising enzymes and the risk of therapy-related leukaemia. Br J Haematol 2007; 136:590.
  93. Chen H, Sandler DP, Taylor JA, et al. Increased risk for myelodysplastic syndromes in individuals with glutathione transferase theta 1 (GSTT1) gene defect. Lancet 1996; 347:295.
  94. Dahabreh IJ, Giannouli S, Gota V, Voulgarelis M. GSTT1 and GSTM1 polymorphisms and myelodysplastic syndrome risk: a systematic review and meta-analysis. Int J Cancer 2010; 126:1716.
  95. Little JB. Cellular, molecular, and carcinogenic effects of radiation. Hematol Oncol Clin North Am 1993; 7:337.
  96. Ishimaru T, Otake M, Ischimaru M. Dose-response relationship of neutrons and gamma rays to leukemia incidence among atomic bomb survivors in Hiroshima and Nagasaki by type of leukemia, 1950--1971. Radiat Res 1979; 77:377.
  97. Bizzozero OJ Jr, Johnson KG, Ciocco A. Radiation-related leukemia in Hiroshima and Nagasaki, 1946-1964. I. Distribution, incidence and appearance time. N Engl J Med 1966; 274:1095.
  98. Yoshinaga S, Mabuchi K, Sigurdson AJ, et al. Cancer risks among radiologists and radiologic technologists: review of epidemiologic studies. Radiology 2004; 233:313.
  99. Shuryak I, Sachs RK, Hlatky L, et al. Radiation-induced leukemia at doses relevant to radiation therapy: modeling mechanisms and estimating risks. J Natl Cancer Inst 2006; 98:1794.
  100. Kaldor JM, Day NE, Band P, et al. Second malignancies following testicular cancer, ovarian cancer and Hodgkin's disease: an international collaborative study among cancer registries. Int J Cancer 1987; 39:571.
  101. Thirman MJ, Larson RA. Therapy-related myeloid leukemia. Hematol Oncol Clin North Am 1996; 10:293.
  102. Valagussa P, Santoro A, Fossati-Bellani F, et al. Second acute leukemia and other malignancies following treatment for Hodgkin's disease. J Clin Oncol 1986; 4:830.
  103. Blayney DW, Longo DL, Young RC, et al. Decreasing risk of leukemia with prolonged follow-up after chemotherapy and radiotherapy for Hodgkin's disease. N Engl J Med 1987; 316:710.
  104. van Leeuwen FE, Somers R, Taal BG, et al. Increased risk of lung cancer, non-Hodgkin's lymphoma, and leukemia following Hodgkin's disease. J Clin Oncol 1989; 7:1046.
  105. Andrieu JM, Ifrah N, Payen C, et al. Increased risk of secondary acute nonlymphocytic leukemia after extended-field radiation therapy combined with MOPP chemotherapy for Hodgkin's disease. J Clin Oncol 1990; 8:1148.
  106. Pearce MS, Salotti JA, Little MP, et al. Radiation exposure from CT scans in childhood and subsequent risk of leukaemia and brain tumours: a retrospective cohort study. Lancet 2012; 380:499.
  107. Brandt L, Nilsson PG, Mitelman F. Occupational exposure to petroleum products in men with acute non-lymphocytic leukaemia. Br Med J 1978; 1:553.
  108. Austin H, Delzell E, Cole P. Benzene and leukemia. A review of the literature and a risk assessment. Am J Epidemiol 1988; 127:419.
  109. Schnatter AR, Glass DC, Tang G, et al. Myelodysplastic syndrome and benzene exposure among petroleum workers: an international pooled analysis. J Natl Cancer Inst 2012; 104:1724.
  110. Rushton L, Schnatter AR, Tang G, Glass DC. Acute myeloid and chronic lymphoid leukaemias and exposure to low-level benzene among petroleum workers. Br J Cancer 2014; 110:783.
  111. Irons RD, Gross SA, Le A, et al. Integrating WHO 2001-2008 criteria for the diagnosis of Myelodysplastic Syndrome (MDS): a case-case analysis of benzene exposure. Chem Biol Interact 2010; 184:30.
  112. Carlos-Wallace FM, Zhang L, Smith MT, et al. Parental, In Utero, and Early-Life Exposure to Benzene and the Risk of Childhood Leukemia: A Meta-Analysis. Am J Epidemiol 2016; 183:1.
  113. Houot J, Marquant F, Goujon S, et al. Residential Proximity to Heavy-Traffic Roads, Benzene Exposure, and Childhood Leukemia-The GEOCAP Study, 2002-2007. Am J Epidemiol 2015; 182:685.
  114. Hauptmann M, Stewart PA, Lubin JH, et al. Mortality from lymphohematopoietic malignancies and brain cancer among embalmers exposed to formaldehyde. J Natl Cancer Inst 2009; 101:1696.
  115. Beane Freeman LE, Blair A, Lubin JH, et al. Mortality from lymphohematopoietic malignancies among workers in formaldehyde industries: the National Cancer Institute Cohort. J Natl Cancer Inst 2009; 101:751.
  116. Bachand AM, Mundt KA, Mundt DJ, Montgomery RR. Epidemiological studies of formaldehyde exposure and risk of leukemia and nasopharyngeal cancer: a meta-analysis. Crit Rev Toxicol 2010; 40:85.
  117. Coggon D, Ntani G, Harris EC, Palmer KT. Upper airway cancer, myeloid leukemia, and other cancers in a cohort of British chemical workers exposed to formaldehyde. Am J Epidemiol 2014; 179:1301.
  118. Linet MS. The Leukemias: Epidemiologic Aspects, Oxford University Press, New York 1985.
  119. Taylor JA, Sandler DP, Bloomfield CD, et al. ras oncogene activation and occupational exposures in acute myeloid leukemia. J Natl Cancer Inst 1992; 84:1626.
  120. Sandler DP, Shore DL, Anderson JR, et al. Cigarette smoking and risk of acute leukemia: associations with morphology and cytogenetic abnormalities in bone marrow. J Natl Cancer Inst 1993; 85:1994.
  121. Smith MT, Wang Y, Kane E, et al. Low NAD(P)H:quinone oxidoreductase 1 activity is associated with increased risk of acute leukemia in adults. Blood 2001; 97:1422.
  122. Larson RA, Wang Y, Banerjee M, et al. Prevalence of the inactivating 609C-->T polymorphism in the NAD(P)H:quinone oxidoreductase (NQO1) gene in patients with primary and therapy-related myeloid leukemia. Blood 1999; 94:803.
  123. Rothman N, Smith MT, Hayes RB, et al. Benzene poisoning, a risk factor for hematological malignancy, is associated with the NQO1 609C-->T mutation and rapid fractional excretion of chlorzoxazone. Cancer Res 1997; 57:2839.
  124. Lebailly P, Willett EV, Moorman AV, et al. Genetic polymorphisms in microsomal epoxide hydrolase and susceptibility to adult acute myeloid leukaemia with defined cytogenetic abnormalities. Br J Haematol 2002; 116:587.
  125. Moorman AV, Roman E, Cartwright RA, Morgan GJ. Smoking and the risk of acute myeloid leukaemia in cytogenetic subgroups. Br J Cancer 2002; 86:60.
  126. Kristinsson SY, Björkholm M, Hultcrantz M, et al. Chronic immune stimulation might act as a trigger for the development of acute myeloid leukemia or myelodysplastic syndromes. J Clin Oncol 2011; 29:2897.
  127. Ross JA, Blair CK, Cerhan JR, et al. Nonsteroidal anti-inflammatory drug and acetaminophen use and risk of adult myeloid leukemia. Cancer Epidemiol Biomarkers Prev 2011; 20:1741.
  128. Walter RB, Milano F, Brasky TM, White E. Long-term use of acetaminophen, aspirin, and other nonsteroidal anti-inflammatory drugs and risk of hematologic malignancies: results from the prospective Vitamins and Lifestyle (VITAL) study. J Clin Oncol 2011; 29:2424.
  129. Poiesz BJ, Ruscetti FW, Gazdar AF, et al. Detection and isolation of type C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma. Proc Natl Acad Sci U S A 1980; 77:7415.
  130. Gallo R, Ruscetti F, Collins S, et al. Human myeloid leukemia cells: Studies on oncornaviral related information and in vitro growth and differentiation. In: Hematopoietic Cell Differentiation, Golde D, Cline M, Metcalf D, et al. (Eds), Academic Press, Orlando 1979. Vol 10, p.335.
  131. Goldin LR, Kristinsson SY, Liang XS, et al. Familial aggregation of acute myeloid leukemia and myelodysplastic syndromes. J Clin Oncol 2012; 30:179.
  132. Miyauchi J, Kelleher CA, Yang YC, et al. The effects of three recombinant growth factors, IL-3, GM-CSF, and G-CSF, on the blast cells of acute myeloblastic leukemia maintained in short-term suspension culture. Blood 1987; 70:657.
  133. Delwel R, Salem M, Pellens C, et al. Growth regulation of human acute myeloid leukemia: effects of five recombinant hematopoietic factors in a serum-free culture system. Blood 1988; 72:1944.
  134. Vellenga E, Ostapovicz D, O'Rourke B, Griffin JD. Effects of recombinant IL-3, GM-CSF, and G-CSF on proliferation of leukemic clonogenic cells in short-term and long-term cultures. Leukemia 1987; 1:584.
  135. Ikeda H, Kanakura Y, Tamaki T, et al. Expression and functional role of the proto-oncogene c-kit in acute myeloblastic leukemia cells. Blood 1991; 78:2962.
  136. Piacibello W, Fubini L, Sanavio F, et al. Effects of human FLT3 ligand on myeloid leukemia cell growth: heterogeneity in response and synergy with other hematopoietic growth factors. Blood 1995; 86:4105.
  137. Meshinchi S, Appelbaum FR. Structural and functional alterations of FLT3 in acute myeloid leukemia. Clin Cancer Res 2009; 15:4263.
  138. Dong F, Brynes RK, Tidow N, et al. Mutations in the gene for the granulocyte colony-stimulating-factor receptor in patients with acute myeloid leukemia preceded by severe congenital neutropenia. N Engl J Med 1995; 333:487.
  139. Dong F, Dale DC, Bonilla MA, et al. Mutations in the granulocyte colony-stimulating factor receptor gene in patients with severe congenital neutropenia. Leukemia 1997; 11:120.
  140. Wölfler A, Erkeland SJ, Bodner C, et al. A functional single-nucleotide polymorphism of the G-CSF receptor gene predisposes individuals to high-risk myelodysplastic syndrome. Blood 2005; 105:3731.
  141. Hunter MG, Avalos BR. Granulocyte colony-stimulating factor receptor mutations in severe congenital neutropenia transforming to acute myelogenous leukemia confer resistance to apoptosis and enhance cell survival. Blood 2000; 95:2132.
  142. Young DC, Griffin JD. Autocrine secretion of GM-CSF in acute myeloblastic leukemia. Blood 1986; 68:1178.
  143. Cozzolino F, Rubartelli A, Aldinucci D, et al. Interleukin 1 as an autocrine growth factor for acute myeloid leukemia cells. Proc Natl Acad Sci U S A 1989; 86:2369.
  144. Löwenberg B, van Putten WL, Touw IP, et al. Autonomous proliferation of leukemic cells in vitro as a determinant of prognosis in adult acute myeloid leukemia. N Engl J Med 1993; 328:614.
  145. Hunter AE, Rogers SY, Roberts IA, et al. Autonomous growth of blast cells is associated with reduced survival in acute myeloblastic leukemia. Blood 1993; 82:899.
  146. Wetzler M, Baer MR, Bernstein SH, et al. Expression of c-mpl mRNA, the receptor for thrombopoietin, in acute myeloid leukemia blasts identifies a group of patients with poor response to intensive chemotherapy. J Clin Oncol 1997; 15:2262.
  147. Koistinen P, Wang C, Curtis JE, McCulloch EA. Granulocyte-macrophage colony-stimulating factor and interleukin-3 protect leukemic blast cells from ara-C toxicity. Leukemia 1991; 5:789.
  148. Lotem J, Sachs L. Hematopoietic cytokines inhibit apoptosis induced by transforming growth factor beta 1 and cancer chemotherapy compounds in myeloid leukemic cells. Blood 1992; 80:1750.
  149. Lisovsky M, Estrov Z, Zhang X, et al. Flt3 ligand stimulates proliferation and inhibits apoptosis of acute myeloid leukemia cells: regulation of Bcl-2 and Bax. Blood 1996; 88:3987.
  150. Geller RB. Use of cytokines in the treatment of acute myelocytic leukemia: a critical review. J Clin Oncol 1996; 14:1371.
  151. Hershman D, Neugut AI, Jacobson JS, et al. Acute myeloid leukemia or myelodysplastic syndrome following use of granulocyte colony-stimulating factors during breast cancer adjuvant chemotherapy. J Natl Cancer Inst 2007; 99:196.
  152. Relling MV, Boyett JM, Blanco JG, et al. Granulocyte colony-stimulating factor and the risk of secondary myeloid malignancy after etoposide treatment. Blood 2003; 101:3862.
  153. Lyman GH, Dale DC, Wolff DA, et al. Acute myeloid leukemia or myelodysplastic syndrome in randomized controlled clinical trials of cancer chemotherapy with granulocyte colony-stimulating factor: a systematic review. J Clin Oncol 2010; 28:2914.