KEGG PATHWAY: ko05221

PATHWAY: ko05221

Entry

ko05221                     Pathway

Name

Acute myeloid leukemia

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

ko05221

Acute myeloid leukemia

Disease

H00003

Acute myeloid leukemia

Orthology

K00922

PIK3CA_B_D; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha/beta/delta [EC:2.7.1.153]

K02158

BAD; Bcl-2-antagonist of cell death

K02162

BCL2A1; hematopoietic Bcl-2-related protein A1

K02580

NFKB1; nuclear factor NF-kappa-B p105 subunit

K02620

TCF7, TCF-1; transcription factor 7

K02633

PER2; period circadian protein 2

K02649

PIK3R1_2_3; phosphoinositide-3-kinase regulatory subunit alpha/beta/delta

K02833

HRAS; GTPase HRas

K03099

SOS; son of sevenless

K04364

GRB2; growth factor receptor-bound protein 2

K04365

BRAF; B-Raf proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1]

K04366

RAF1; RAF proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1]

K04368

MAP2K1, MEK1; mitogen-activated protein kinase kinase 1 [EC:2.7.12.2]

K04369

MAP2K2, MEK2; mitogen-activated protein kinase kinase 2 [EC:2.7.12.2]

K04371

ERK, MAPK1_3; mitogen-activated protein kinase 1/3 [EC:2.7.11.24]

K04377

MYC; Myc proto-oncogene protein

K04391

CD14; monocyte differentiation antigen CD14

K04456

AKT; RAC serine/threonine-protein kinase [EC:2.7.11.1]

K04467

IKBKA, IKKA, CHUK; inhibitor of nuclear factor kappa-B kinase subunit alpha [EC:2.7.11.10]

K04490

TCF7L1; transcription factor 7-like 1

K04491

TCF7L2; transcription factor 7-like 2

K04492

LEF1; lymphoid enhancer-binding factor 1

K04503

CCND1; G1/S-specific cyclin-D1

K04504

NR1C2, PPARD; peroxisome proliferator-activated receptor delta

K04688

RPS6KB; ribosomal protein S6 kinase beta [EC:2.7.11.1]

K04692

STAT3; signal transducer and activator of transcription 3

K04702

PIM1; proto-oncogene serine/threonine-protein kinase Pim-1 [EC:2.7.11.1]

K04735

RELA; transcription factor p65

K04736

IL3; interleukin 3

K05090

CSF1R, FMS, CD115; macrophage colony-stimulating factor 1 receptor [EC:2.7.10.1]

K05091

KIT, SCFR, CD117; proto-oncogene tyrosine-protein kinase Kit [EC:2.7.10.1]

K05092

FLT3, FLK2, CD135; fms-related tyrosine kinase 3 [EC:2.7.10.1]

K05427

CSF2, GMCSF; granulocyte-macrophage colony-stimulating factor

K06461

ITGAM, CD11b; integrin alpha M

K06498

FCGR1A, CD64; high affinity immunoglobulin gamma Fc receptor I

K06627

CCNA; cyclin-A

K07203

MTOR, FRAP, TOR; serine/threonine-protein kinase mTOR [EC:2.7.11.1]

K07205

EIF4EBP1; eukaryotic translation initiation factor 4E binding protein 1

K07209

IKBKB, IKKB; inhibitor of nuclear factor kappa-B kinase subunit beta [EC:2.7.11.10]

K07210

IKBKG, IKKG, NEMO; inhibitor of nuclear factor kappa-B kinase subunit gamma

K07827

KRAS, KRAS2; GTPase KRas

K07828

NRAS; GTPase NRas

K08367

RUNX1, AML1; runt-related transcription factor 1

K08527

RARA, NR1B1; retinoic acid receptor alpha

K08806

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

K08845

ARAF, ARAF1; A-Raf proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1]

K09055

CEBPA; CCAAT/enhancer binding protein (C/EBP), alpha

K09438

SPI1; transcription factor PU.1

K10051

CEBPE; CCAAT/enhancer binding protein (C/EBP), epsilon

K10053

RUNX1T1, CBFA2T1; CBFA2/RNUX1 translocation partner 1

K10054

PML, TRIM19; E3 SUMO-protein ligase PML [EC:2.3.2.-]

K10055

ZBTB16, PLZF; zinc finger and BTB domain-containing protein 16

K10056

JUP, PG; junction plakoglobin

K10789

MPO; myeloperoxidase [EC:1.11.2.2]

K11223

STAT5A; signal transducer and activator of transcription 5A

K11224

STAT5B; signal transducer and activator of transcription 5B

K21946

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

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)