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

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]

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]
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

PMID:10502596

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

PMID:16236521

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

PMID:12194988

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

Blood 93:1817-24 (1999)
DOI:10.1182/blood.V93.6.1817.406k36_1817_1824

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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Ontology (2)   
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Pathway (1)   
   KEGG PATHWAY (1)   
Network (30)   
   KEGG NETWORK (21)   
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Drug (33)   
   KEGG DRUG (33)   
Gene (41)   
   KEGG ORTHOLOGY (20)   
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