KEGG PATHWAY: hsa05221

PATHWAY: hsa05221

Entry

hsa05221                    Pathway

Name

Acute myeloid leukemia - Homo sapiens (human)

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 AML-ETO, PML-RARalpha or PLZF-RARalpha block myeloid cell differentiation by repressing target genes. In other cases, the transcription factors themselves are mutated.

Class

Human Diseases; Cancer: specific types

Pathway map

hsa05221

Acute myeloid leukemia

Network

Element

N00003

Mutation-activated KIT to RAS-ERK signaling pathway

N00004

Duplication or mutation-activated FLT3 to RAS-ERK signaling pathway

N00012

Mutation-activated KRAS/NRAS to ERK signaling pathway

N00031

Duplication or mutation-activated FLT3 to RAS-PI3K signaling pathway

N00032

Mutation-activated KRAS/NRAS to PI3K signaling pathway

N00046

Mutation-activated KIT to PI3K signaling pathway

N00054

Duplication or mutation-activated FLT3 to Jak-STAT signaling pathway

N00108

AML1-ETO fusion to transcriptional activtion

N00109

PML-RARA fusion to transcriptional activtion

N00110

PLZF-RARA fusion to transcriptional activtion

N00111

AML1-ETO fusion to CEBPA-mediated transcription

N00112

AML1-ETO fusion to PU.1-mediated transcription

N00113

PML-RARA fusion to transcriptional repression

N00114

PLZF-RARA fusion to transcriptional repression

N00116

Mutation-inactivated RUNX1 to transcription

Disease

H00003

Acute myeloid leukemia

Drug

D00094

Tretinoin (JAN/USP/INN)

D05029

Midostaurin (JAN/USAN/INN)

D10800

Gilteritinib fumarate (JAN/USAN)

D12476

Tuspetinib (USAN/INN)

Organism

Homo sapiens (human) [GN:hsa]

Gene

3815	KIT; KIT proto-oncogene, receptor tyrosine kinase [KO:K05091] [EC:2.7.10.1]

2322	FLT3; fms related receptor tyrosine kinase 3 [KO:K05092] [EC:2.7.10.1]

5290	PIK3CA; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [KO:K00922] [EC:2.7.1.153]

5293	PIK3CD; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [KO:K00922] [EC:2.7.1.153]

5291	PIK3CB; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [KO:K00922] [EC:2.7.1.153]

5295	PIK3R1; phosphoinositide-3-kinase regulatory subunit 1 [KO:K02649]

5296	PIK3R2; phosphoinositide-3-kinase regulatory subunit 2 [KO:K02649]

8503	PIK3R3; phosphoinositide-3-kinase regulatory subunit 3 [KO:K02649]

207	AKT1; AKT serine/threonine kinase 1 [KO:K04456] [EC:2.7.11.1]

208	AKT2; AKT serine/threonine kinase 2 [KO:K04456] [EC:2.7.11.1]

10000

AKT3; AKT serine/threonine kinase 3 [KO:K04456] [EC:2.7.11.1]

1147	CHUK; component of inhibitor of nuclear factor kappa B kinase complex [KO:K04467] [EC:2.7.11.10]

3551	IKBKB; inhibitor of nuclear factor kappa B kinase subunit beta [KO:K07209] [EC:2.7.11.10]

8517	IKBKG; inhibitor of nuclear factor kappa B kinase regulatory subunit gamma [KO:K07210]

4790	NFKB1; nuclear factor kappa B subunit 1 [KO:K02580]

5970	RELA; RELA proto-oncogene, NF-kB subunit [KO:K04735]

572	BAD; BCL2 associated agonist of cell death [KO:K02158]

2475	MTOR; mechanistic target of rapamycin kinase [KO:K07203] [EC:2.7.11.1]

1978	EIF4EBP1; eukaryotic translation initiation factor 4E binding protein 1 [KO:K07205]

6198	RPS6KB1; ribosomal protein S6 kinase B1 [KO:K04688] [EC:2.7.11.1]

6199	RPS6KB2; ribosomal protein S6 kinase B2 [KO:K04688] [EC:2.7.11.1]

2885	GRB2; growth factor receptor bound protein 2 [KO:K04364]

6654	SOS1; SOS Ras/Rac guanine nucleotide exchange factor 1 [KO:K03099]

6655	SOS2; SOS Ras/Rho guanine nucleotide exchange factor 2 [KO:K03099]

3265	HRAS; HRas proto-oncogene, GTPase [KO:K02833]

4893	NRAS; NRAS proto-oncogene, GTPase [KO:K07828]

3845	KRAS; KRAS proto-oncogene, GTPase [KO:K07827]

369	ARAF; A-Raf proto-oncogene, serine/threonine kinase [KO:K08845] [EC:2.7.11.1]

673	BRAF; B-Raf proto-oncogene, serine/threonine kinase [KO:K04365] [EC:2.7.11.1]

5894	RAF1; Raf-1 proto-oncogene, serine/threonine kinase [KO:K04366] [EC:2.7.11.1]

5604	MAP2K1; mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]

5605	MAP2K2; mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]

5594	MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]

5595	MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]

6774	STAT3; signal transducer and activator of transcription 3 [KO:K04692]

6776	STAT5A; signal transducer and activator of transcription 5A [KO:K11223]

6777	STAT5B; signal transducer and activator of transcription 5B [KO:K11224]

5292	PIM1; Pim-1 proto-oncogene, serine/threonine kinase [KO:K04702] [EC:2.7.11.1]

11040

PIM2; Pim-2 proto-oncogene, serine/threonine kinase [KO:K08806] [EC:2.7.11.1]

861	RUNX1; RUNX family transcription factor 1 [KO:K08367]

1436	CSF1R; colony stimulating factor 1 receptor [KO:K05090] [EC:2.7.10.1]

4353	MPO; myeloperoxidase [KO:K10789] [EC:1.11.2.2]

1437	CSF2; colony stimulating factor 2 [KO:K05427]

3562	IL3; interleukin 3 [KO:K04736]

862	RUNX1T1; RUNX1 partner transcriptional co-repressor 1 [KO:K10053]

5371	PML; PML nuclear body scaffold [KO:K10054] [EC:2.3.2.-]

5914	RARA; retinoic acid receptor alpha [KO:K08527]

7704	ZBTB16; zinc finger and BTB domain containing 16 [KO:K10055]

1050	CEBPA; CCAAT enhancer binding protein alpha [KO:K09055]

8864	PER2; period circadian regulator 2 [KO:K02633]

6688	SPI1; Spi-1 proto-oncogene [KO:K09438]

929	CD14; CD14 molecule [KO:K04391]

3684	ITGAM; integrin subunit alpha M [KO:K06461]

2209	FCGR1A; Fc gamma receptor Ia [KO:K06498]

1053	CEBPE; CCAAT enhancer binding protein epsilon [KO:K10051]

597	BCL2A1; BCL2 related protein A1 [KO:K02162]

890	CCNA2; cyclin A2 [KO:K06627]

8900	CCNA1; cyclin A1 [KO:K06627]

4609	MYC; MYC proto-oncogene, bHLH transcription factor [KO:K04377]

1848	DUSP6; dual specificity phosphatase 6 [KO:K21946] [EC:3.1.3.16 3.1.3.48]

3728	JUP; junction plakoglobin [KO:K10056]

6932	TCF7; transcription factor 7 [KO:K02620]

83439

TCF7L1; transcription factor 7 like 1 [KO:K04490]

6934	TCF7L2; transcription factor 7 like 2 [KO:K04491]

51176

LEF1; lymphoid enhancer binding factor 1 [KO:K04492]

595	CCND1; cyclin D1 [KO:K04503]

5467	PPARD; peroxisome proliferator activated receptor delta [KO:K04504]

Compound

C05981

Phosphatidylinositol-3,4,5-trisphosphate

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:12563308

Authors

Tenen DG.

Title

Disruption of differentiation in human cancer: AML shows the way.

Journal

Nat Rev Cancer 3:89-101 (2003)
DOI:10.1038/nrc989

Reference

PMID:16146838

Authors

Choudhary C, Muller-Tidow C, Berdel WE, Serve H.

Title

Signal transduction of oncogenic Flt3.

Journal

Int J Hematol 82:93-9 (2005)
DOI:10.1532/IJH97.05090

Reference

PMID:12951584

Authors

Stirewalt DL, Radich JP.

Title

The role of FLT3 in haematopoietic malignancies.

Journal

Nat Rev Cancer 3:650-65 (2003)
DOI:10.1038/nrc1169

Reference

PMID:16642045

Authors

Martelli AM, Nyakern M, Tabellini G, Bortul R, Tazzari PL, Evangelisti C, Cocco L.

Title

Phosphoinositide 3-kinase/Akt signaling pathway and its therapeutical implications for human acute myeloid leukemia.

Journal

Leukemia 20:911-28 (2006)
DOI:10.1038/sj.leu.2404245

Reference

PMID:15625120

Authors

Lennartsson J, Jelacic T, Linnekin D, Shivakrupa R.

Title

Normal and oncogenic forms of the receptor tyrosine kinase kit.

Journal

Stem Cells 23:16-43 (2005)
DOI:10.1634/stemcells.2004-0117

Reference

PMID:11721960

Authors

Lorsbach RB, Downing JR.

Title

The role of the AML1 transcription factor in leukemogenesis.

Journal

Int J Hematol 74:258-65 (2001)
DOI:10.1007/BF02982058

Reference

PMID:12468433

Authors

Mizuki M, Schwable J, Steur C, Choudhary C, Agrawal S, Sargin B, Steffen B, Matsumura I, Kanakura Y, Bohmer FD, Muller-Tidow C, Berdel WE, Serve H.

Title

Suppression of myeloid transcription factors and induction of STAT response genes by AML-specific Flt3 mutations.

Journal

Blood 101:3164-73 (2003)
DOI:10.1182/blood-2002-06-1677

Reference

PMID:16352814

Authors

Mueller BU, Pabst T, Fos J, Petkovic V, Fey MF, Asou N, Buergi U, Tenen DG.

Title

ATRA resolves the differentiation block in t(15;17) acute myeloid leukemia by restoring PU.1 expression.

Journal

Blood 107:3330-8 (2006)
DOI:10.1182/blood-2005-07-3068

Reference

PMID:12529654

Authors

Roumier C, Fenaux P, Lafage M, Imbert M, Eclache V, Preudhomme C

Title

New mechanisms of AML1 gene alteration in hematological malignancies.

Journal

Leukemia 17:9-16 (2003)
DOI:10.1038/sj.leu.2402766

Reference

PMID:12032780

Authors

Scandura JM, Boccuni P, Cammenga J, Nimer SD

Title

Transcription factor fusions in acute leukemia: variations on a theme.

Journal

Oncogene 21:3422-44 (2002)
DOI:10.1038/sj.onc.1205315

Reference

PMID:10717473

Authors

Lutterbach B, Hiebert SW

Title

Role of the transcription factor AML-1 in acute leukemia and hematopoietic differentiation.

Journal

Gene 245:223-35 (2000)
DOI:10.1016/S0378-1119(00)00014-7

Reference

PMID:19075268

Authors

Koschmieder S, Halmos B, Levantini E, Tenen DG

Title

Dysregulation of the C/EBPalpha differentiation pathway in human cancer.

Journal

J Clin Oncol 27:619-28 (2009)
DOI:10.1200/JCO.2008.17.9812

Reference

PMID:15985538

Authors

Gery S, Gombart AF, Yi WS, Koeffler C, Hofmann WK, Koeffler HP

Title

Transcription profiling of C/EBP targets identifies Per2 as a gene implicated in myeloid leukemia.

Journal

Blood 106:2827-36 (2005)
DOI:10.1182/blood-2005-01-0358

Reference

PMID:12130514

Authors

Mueller BU, Pabst T, Osato M, Asou N, Johansen LM, Minden MD, Behre G, Hiddemann W, Ito Y, Tenen DG

Title

Heterozygous PU.1 mutations are associated with acute myeloid leukemia.

Journal

Blood 100:998-1007 (2002)
DOI:10.1182/blood.V100.3.998

Reference

PMID:12393465

Authors

Vangala RK, Heiss-Neumann MS, Rangatia JS, Singh SM, Schoch C, Tenen DG, Hiddemann W, Behre G

Title

The myeloid master regulator transcription factor PU.1 is inactivated by AML1-ETO in t(8;21) myeloid leukemia.

Journal

Blood 101:270-7 (2003)
DOI:10.1182/blood-2002-04-1288

Reference

PMID:15024077

Authors

Muller-Tidow C, Steffen B, Cauvet T, Tickenbrock L, Ji P, Diederichs S, Sargin B, Kohler G, Stelljes M, Puccetti E, Ruthardt M, deVos S, Hiebert SW, Koeffler HP, Berdel WE, Serve H

Title

Translocation products in acute myeloid leukemia activate the Wnt signaling pathway in hematopoietic cells.

Journal

Mol Cell Biol 24:2890-904 (2004)
DOI:10.1128/MCB.24.7.2890-2904.2004

Reference

PMID:11090075

Authors

Muller C, Yang R, Park DJ, Serve H, Berdel WE, Koeffler HP

Title

The aberrant fusion proteins PML-RAR alpha and PLZF-RAR alpha contribute to the overexpression of cyclin A1 in acute promyelocytic leukemia.

Journal

Blood 96:3894-9 (2000)