KEGG   DISEASE: Acute myeloid leukemia
Entry
H00003                      Disease                                
Name
Acute myeloid leukemia
  Subgroup
Acute promyelocytic leukemia [DS:H02542]
Description
Acute myeloid leukemia (AML) is a disease that is characterized by uncontrolled proliferation of clonal neoplastic cells and accumulation in the bone marrow of blasts with an impaired differentiation program. AML accounts for approximately 80% of all adult leukemias and remains the most common cause of leukemia death. Two major types of genetic events have been described that are crucial for leukemic transformation. A proposed necessary first event is disordered cell growth and upregulation of cell survival genes. The most common of these activating events were observed in the RTK Flt3, in N-Ras and K-Ras, in Kit, and sporadically in other RTKs. Alterations in myeloid transcription factors governing hematopoietic differentiation provide second necessary event for leukemogenesis. Transcription factor fusion proteins such as PML-RARalpha (in Acute promyelocytic leukemia, a subtype of AML), AML-ETO or PLZF-RARalpha block myeloid cell differentiation by repressing target genes. In other cases, the transcription factors themselves are mutated.
Category
Cancer
Brite
Human diseases [BR:br08402]
 Cancers
  Cancers of haematopoietic and lymphoid tissues
   H00003  Acute myeloid leukemia
Human diseases in ICD-11 classification [BR:br08403]
 02 Neoplasms
  Neoplasms of haematopoietic or lymphoid tissues
   2A60  Acute myeloid leukaemias and related precursor neoplasms
    H00003  Acute myeloid leukemia
Tumor markers [br08442.html]
 H00003
Cancer-associated carbohydrates [br08441.html]
 H00003
Pathway
hsa05221  Acute myeloid leukemia
Related
pathway
hsa05200  Pathways in cancer
hsa05202  Transcriptional misregulation in cancer
Network
nt06275  Acute myeloid leukemia
Gene
PML-RARalpha (translocation) [HSA:5371] [KO:K10054]
AML1-ETO (translocation) [HSA:861] [KO:K08367]
PLZF-RARalpha (translocation) [HSA:7704] [KO:K10055]
FLT3 [HSA:2322] [KO:K05092]
KIT [HSA:3815] [KO:K05091]
NRAS [HSA:4893] [KO:K07828]
KRAS [HSA:3845] [KO:K07827]
AML1 [HSA:861] [KO:K08367]
CEBPA [HSA:1050] [KO:K09055]
CBFB [HSA:865] [KO:K25826]
CHIC2 [HSA:26511]
DNMT3A [HSA:1788] [KO:K17398]
ETV6 [HSA:2120] [KO:K03211]
GATA2 [HSA:2624] [KO:K17894]
JAK2 [HSA:3717] [KO:K04447]
LPP [HSA:4026] [KO:K16676]
MLLT10 [HSA:8028] [KO:K23588]
NPM1 [HSA:4869] [KO:K11276]
NUP214 [HSA:8021] [KO:K14317]
PICALM [HSA:8301] [KO:K20044]
SH3GL1 [HSA:6455] [KO:K11247]
TERT [HSA:7015] [KO:K11126]
Carcinogen
Benzene [CPD:C01407]
1,4-Butanediol dimethanesulfonate (Busulphan; Myleran) [CPD:C06862]
Chlorambucil [CPD:C06900]
Cyclophosphamide [CPD:C07888]
Ethylene oxide [CPD:C06548]
Melphalan [CPD:C07122]
Thiotepa [CPD:C07641]
Drug
Cyclophosphamide [DR:D00287]
Thioguanine [DR:D06109]
Cytarabine [DR:D00168]
Doxorubicin hydrochloride [DR:D01275]
Daunorubicin hydrochloride [DR:D01264]
Idarubicin hydrochloride [DR:D01747]
Mitoxantrone hydrochloride [DR:D02166]
Midostaurin [DR:D05029] (FLT3 mutation-positive)
Gilteritinib fumarate [DR:D10800] (FLT3 mutation-positive)
Gemtuzumab ozogamicin [DR:D03259] (CD33-positive)
Glasdegib maleate [DR:D11107]
Arsenic trioxide [DR:D02106]
Venetoclax [DR:D10679]
Enasidenib mesylate [DR:D11044] (IDH2 mutation positive)
Ivosidenib [DR:D11090] (susceptible IDH1 mutation)
Daunorubicin and cytarabine [DR:D11390]
Sargramostim [DR:D05803]
Enocitabine [DR:D01633]
Other DBs
ICD-11: 2A60
ICD-10: C92.0
MeSH: D015470
Reference
  Authors
Lowenberg B, Downing JR, Burnett A.
  Title
Acute myeloid leukemia.
  Journal
N Engl J Med 341:1051-62 (1999)
DOI:10.1056/NEJM199909303411407
Reference
  Authors
Steffen B, Muller-Tidow C, Schwable J, Berdel WE, Serve H.
  Title
The molecular pathogenesis of acute myeloid leukemia.
  Journal
Crit Rev Oncol Hematol 56:195-221 (2005)
DOI:10.1016/j.critrevonc.2004.10.012
Reference
  Authors
Kelly LM, Gilliland DG.
  Title
Genetics of myeloid leukemias.
  Journal
Annu Rev Genomics Hum Genet 3:179-98 (2002)
DOI:10.1146/annurev.genom.3.032802.115046
Reference
PMID:1652369 (PML-RARalpha translocation)
  Authors
de The H, Lavau C, Marchio A, Chomienne C, Degos L, Dejean A
  Title
The PML-RAR alpha fusion mRNA generated by the t(15;17) translocation in acute promyelocytic leukemia encodes a functionally altered RAR.
  Journal
Cell 66:675-84 (1991)
DOI:10.1016/0092-8674(91)90113-D
Reference
PMID:1391946 (AML1-ETO translocation)
  Authors
Erickson P, Gao J, Chang KS, Look T, Whisenant E, Raimondi S, Lasher R, Trujillo J, Rowley J, Drabkin H
  Title
Identification of breakpoints in t(8;21) acute myelogenous leukemia and isolation of a fusion transcript, AML1/ETO, with similarity to Drosophila segmentation gene, runt.
  Journal
Blood 80:1825-31 (1992)
DOI:10.1182/blood.V80.7.1825.1825
Reference
PMID:8622986 (PLZF-RARalpha translocation)
  Authors
Dong S, Zhu J, Reid A, Strutt P, Guidez F, Zhong HJ, Wang ZY, Licht J, Waxman S, Chomienne C, Chen Z, Zelent A, Chen SJ
  Title
Amino-terminal protein-protein interaction motif (POZ-domain) is responsible for activities of the promyelocytic leukemia zinc finger-retinoic acid receptor-alpha fusion protein.
  Journal
Proc Natl Acad Sci U S A 93:3624-9 (1996)
DOI:10.1073/pnas.93.8.3624
Reference
PMID:16757428 (FLT3)
  Authors
Kiyoi H, Naoe T.
  Title
Biology, clinical relevance, and molecularly targeted therapy in acute leukemia with FLT3 mutation.
  Journal
Int J Hematol 83:301-8 (2006)
DOI:10.1532/IJH97.06071
Reference
PMID:9657776 (KIT)
  Authors
Beghini A, Larizza L, Cairoli R, Morra E
  Title
c-kit activating mutations and mast cell proliferation in human leukemia.
  Journal
Blood 92:701-2 (1998)
DOI:10.1182/blood.V92.2.701
Reference
PMID:23634996 (NRAS)
  Authors
Ley TJ, Miller C, Ding L, Raphael BJ, Mungall AJ, Robertson A, Hoadley K, Triche TJ Jr, Laird PW, Baty JD, Fulton LL, Fulton R, Heath SE, Kalicki-Veizer J, Kandoth C, Klco JM, Koboldt DC, Kanchi KL, Kulkarni S, Lamprecht TL, Larson DE, Lin L, Lu C, McLellan MD, McMichael JF, Payton J, Schmidt H, Spencer DH, Tomasson MH, Wallis JW, Wartman LD, Watson MA, Welch J, Wendl MC, Ally A, Balasundaram M, Birol I, Butterfield Y, Chiu R, Chu A, Chuah E, Chun HJ, Corbett R, Dhalla N, Guin R, He A, Hirst C, Hirst M, Holt RA, Jones S, Karsan A, Lee D, Li HI, Marra MA, Mayo M, Moore RA, Mungall K, Parker J, Pleasance E, Plettner P, Schein J, Stoll D, Swanson L, Tam A, Thiessen N, Varhol R, Wye N, Zhao Y, Gabriel S, Getz G, Sougnez C, Zou L, Leiserson MD, Vandin F, Wu HT, Applebaum F, Baylin SB, Akbani R, Broom BM, Chen K, Motter TC, Nguyen K, Weinstein JN, Zhang N, Ferguson ML, Adams C, Black A, Bowen J, Gastier-Foster J, Grossman T, Lichtenberg T, Wise L, Davidsen T, Demchok JA, Shaw KR, Sheth M, Sofia HJ, Yang L, Downing JR, Eley G
  Title
Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia.
  Journal
N Engl J Med 368:2059-74 (2013)
DOI:10.1056/NEJMoa1301689
Reference
PMID:8955068 (KRAS)
  Authors
Bollag G, Adler F, elMasry N, McCabe PC, Conner E Jr, Thompson P, McCormick F, Shannon K
  Title
Biochemical characterization of a novel KRAS insertion mutation from a human leukemia.
  Journal
J Biol Chem 271:32491-4 (1996)
DOI:10.1074/jbc.271.51.32491
Reference
PMID:10068652 (AML1)
  Authors
Osato M, Asou N, Abdalla E, Hoshino K, Yamasaki H, Okubo T, Suzushima H, Takatsuki K, Kanno T, Shigesada K, Ito Y
  Title
Biallelic and heterozygous point mutations in the runt domain of the AML1/PEBP2alphaB gene associated with myeloblastic leukemias.
  Journal
Reference
PMID:15575056 (CEBPA)
  Authors
Smith ML, Cavenagh JD, Lister TA, Fitzgibbon J
  Title
Mutation of CEBPA in familial acute myeloid leukemia.
  Journal
N Engl J Med 351:2403-7 (2004)
DOI:10.1056/NEJMoa041331
Reference
PMID:25678665 (CBFB)
  Authors
Illendula A, Pulikkan JA, Zong H, Grembecka J, Xue L, Sen S, Zhou Y, Boulton A, Kuntimaddi A, Gao Y, Rajewski RA, Guzman ML, Castilla LH, Bushweller JH
  Title
Chemical biology. A small-molecule inhibitor of the aberrant transcription factor CBFbeta-SMMHC delays leukemia in mice.
  Journal
Science 347:779-84 (2015)
DOI:10.1126/science.aaa0314
Reference
PMID:10477709 (CHIC2)
  Authors
Cools J, Bilhou-Nabera C, Wlodarska I, Cabrol C, Talmant P, Bernard P, Hagemeijer A, Marynen P
  Title
Fusion of a novel gene, BTL, to ETV6 in acute myeloid leukemias with a t(4;12)(q11-q12;p13).
  Journal
Blood 94:1820-4 (1999)
DOI:10.1182/blood.V94.5.1820
Reference
PMID:21067377 (DNMT3A)
  Authors
Ley TJ, Ding L, Walter MJ, McLellan MD, Lamprecht T, Larson DE, Kandoth C, Payton JE, Baty J, Welch J, Harris CC, Lichti CF, Townsend RR, Fulton RS, Dooling DJ, Koboldt DC, Schmidt H, Zhang Q, Osborne JR, Lin L, O'Laughlin M, McMichael JF, Delehaunty KD, McGrath SD, Fulton LA, Magrini VJ, Vickery TL, Hundal J, Cook LL, Conyers JJ, Swift GW, Reed JP, Alldredge PA, Wylie T, Walker J, Kalicki J, Watson MA, Heath S, Shannon WD, Varghese N, Nagarajan R, Westervelt P, Tomasson MH, Link DC, Graubert TA, DiPersio JF, Mardis ER, Wilson RK
  Title
DNMT3A mutations in acute myeloid leukemia.
  Journal
N Engl J Med 363:2424-33 (2010)
DOI:10.1056/NEJMoa1005143
Reference
PMID:25581430 (ETV6)
  Authors
Zhang MY, Churpek JE, Keel SB, Walsh T, Lee MK, Loeb KR, Gulsuner S, Pritchard CC, Sanchez-Bonilla M, Delrow JJ, Basom RS, Forouhar M, Gyurkocza B, Schwartz BS, Neistadt B, Marquez R, Mariani CJ, Coats SA, Hofmann I, Lindsley RC, Williams DA, Abkowitz JL, Horwitz MS, King MC, Godley LA, Shimamura A
  Title
Germline ETV6 mutations in familial thrombocytopenia and hematologic malignancy.
  Journal
Nat Genet 47:180-5 (2015)
DOI:10.1038/ng.3177
Reference
PMID:21892162 (GATA2)
  Authors
Hahn CN, Chong CE, Carmichael CL, Wilkins EJ, Brautigan PJ, Li XC, Babic M, Lin M, Carmagnac A, Lee YK, Kok CH, Gagliardi L, Friend KL, Ekert PG, Butcher CM, Brown AL, Lewis ID, To LB, Timms AE, Storek J, Moore S, Altree M, Escher R, Bardy PG, Suthers GK, D'Andrea RJ, Horwitz MS, Scott HS
  Title
Heritable GATA2 mutations associated with familial myelodysplastic syndrome and acute myeloid leukemia.
  Journal
Nat Genet 43:1012-7 (2011)
DOI:10.1038/ng.913
Reference
PMID:16247455 (JAK2)
  Authors
Lee JW, Kim YG, Soung YH, Han KJ, Kim SY, Rhim HS, Min WS, Nam SW, Park WS, Lee JY, Yoo NJ, Lee SH
  Title
The JAK2 V617F mutation in de novo acute myelogenous leukemias.
  Journal
Oncogene 25:1434-6 (2006)
DOI:10.1038/sj.onc.1209163
Reference
PMID:11433529 (LPP)
  Authors
Daheron L, Veinstein A, Brizard F, Drabkin H, Lacotte L, Guilhot F, Larsen CJ, Brizard A, Roche J
  Title
Human LPP gene is fused to MLL in a secondary acute leukemia with a t(3;11) (q28;q23).
  Journal
Genes Chromosomes Cancer 31:382-9 (2001)
DOI:10.1002/gcc.1157
Reference
PMID:8896421 (MLLT10)
  Authors
Tanabe S, Bohlander SK, Vignon CV, Espinosa R 3rd, Zhao N, Strissel PL, Zeleznik-Le NJ, Rowley JD
  Title
AF10 is split by MLL and HEAB, a human homolog to a putative Caenorhabditis elegans ATP/GTP-binding protein in an invins(10;11)(p12;q23q12).
  Journal
Blood 88:3535-45 (1996)
Reference
PMID:18308931 (NPM1)
  Authors
Garzon R, Garofalo M, Martelli MP, Briesewitz R, Wang L, Fernandez-Cymering C, Volinia S, Liu CG, Schnittger S, Haferlach T, Liso A, Diverio D, Mancini M, Meloni G, Foa R, Martelli MF, Mecucci C, Croce CM, Falini B
  Title
Distinctive microRNA signature of acute myeloid leukemia bearing cytoplasmic mutated nucleophosmin.
  Journal
Proc Natl Acad Sci U S A 105:3945-50 (2008)
DOI:10.1073/pnas.0800135105
Reference
PMID:2370860 (NUP214)
  Authors
von Lindern M, Poustka A, Lerach H, Grosveld G
  Title
The (6;9) chromosome translocation, associated with a specific subtype of acute nonlymphocytic leukemia, leads to aberrant transcription of a target gene on 9q34.
  Journal
Mol Cell Biol 10:4016-26 (1990)
DOI:10.1128/mcb.10.8.4016-4026.1990
Reference
PMID:10637483 (PICALM)
  Authors
Carlson KM, Vignon C, Bohlander S, Martinez-Climent JA, Le Beau MM, Rowley JD
  Title
Identification and molecular characterization of CALM/AF10fusion products in T cell acute lymphoblastic leukemia and acute myeloid leukemia.
  Journal
Leukemia 14:100-4 (2000)
DOI:10.1038/sj.leu.2401629
Reference
PMID:9122235 (SH3GL1)
  Authors
So CW, Caldas C, Liu MM, Chen SJ, Huang QH, Gu LJ, Sham MH, Wiedemann LM, Chan LC
  Title
EEN encodes for a member of a new family of proteins containing an Src homology 3 domain and is the third gene located on chromosome 19p13 that fuses to MLL in human leukemia.
  Journal
Proc Natl Acad Sci U S A 94:2563-8 (1997)
DOI:10.1073/pnas.94.6.2563
Reference
PMID:19147845 (TERT)
  Authors
Calado RT, Regal JA, Hills M, Yewdell WT, Dalmazzo LF, Zago MA, Lansdorp PM, Hogge D, Chanock SJ, Estey EH, Falcao RP, Young NS
  Title
Constitutional hypomorphic telomerase mutations in patients with acute myeloid leukemia.
  Journal
Proc Natl Acad Sci U S A 106:1187-92 (2009)
DOI:10.1073/pnas.0807057106

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