KEGG PATHWAY: ptr05221

PATHWAY: ptr05221

Entry

ptr05221                    Pathway

Name

Acute myeloid leukemia - Pan troglodytes (chimpanzee)

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

ptr05221

Acute myeloid leukemia

Organism

Pan troglodytes (chimpanzee) [GN:ptr]

Gene

461316

KIT; mast/stem cell growth factor receptor Kit isoform X1 [KO:K05091] [EC:2.7.10.1]

452508

FLT3; receptor-type tyrosine-protein kinase FLT3 [KO:K05092] [EC:2.7.10.1]

460858

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

457922

PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]

471079

PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]

456565

PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform X2 [KO:K02649]

461836

PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X2 [KO:K02649]

455855

PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]

456035

AKT2; RAC-beta serine/threonine-protein kinase isoform X4 [KO:K04456] [EC:2.7.11.1]

740898

AKT1; RAC-alpha serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]

100609583

AKT3; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]

450673

CHUK; inhibitor of nuclear factor kappa-B kinase subunit alpha [KO:K04467] [EC:2.7.11.10]

472749

IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta isoform X1 [KO:K07209] [EC:2.7.11.10]

100610002

NF-kappa-B essential modulator [KO:K07210]

100609537

IKBKG; LOW QUALITY PROTEIN: NF-kappa-B essential modulator [KO:K07210]

461406

NFKB1; nuclear factor NF-kappa-B p105 subunit isoform X3 [KO:K02580]

466665

RELA; transcription factor p65 [KO:K04735]

100615623

BAD; bcl2-associated agonist of cell death [KO:K02158]

457945

MTOR; serine/threonine-protein kinase mTOR isoform X1 [KO:K07203] [EC:2.7.11.1]

464114

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

468426

RPS6KB1; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]

746903

RPS6KB2; ribosomal protein S6 kinase beta-2 [KO:K04688] [EC:2.7.11.1]

737245

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

459171

SOS1; son of sevenless homolog 1 isoform X2 [KO:K03099]

452897

SOS2; son of sevenless homolog 2 isoform X1 [KO:K03099]

466302

HRAS; GTPase HRas isoform X1 [KO:K02833]

742713

NRAS; GTPase NRas [KO:K07828]

473387

KRAS; GTPase KRas isoform X1 [KO:K07827]

100614256

ARAF; serine/threonine-protein kinase A-Raf isoform X1 [KO:K08845] [EC:2.7.11.1]

463781

BRAF; serine/threonine-protein kinase B-raf isoform X2 [KO:K04365] [EC:2.7.11.1]

460182

RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X2 [KO:K04366] [EC:2.7.11.1]

450188

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

456390

MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 isoform X1 [KO:K04369] [EC:2.7.12.2]

454037

MAPK3; mitogen-activated protein kinase 3 isoform X1 [KO:K04371] [EC:2.7.11.24]

458680

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

454682

STAT3; signal transducer and activator of transcription 3 isoform X8 [KO:K04692]

454681

STAT5A; signal transducer and activator of transcription 5A isoform X1 [KO:K11223]

454679

STAT5B; signal transducer and activator of transcription 5B isoform X1 [KO:K11224]

462656

PIM1; serine/threonine-protein kinase pim-1 [KO:K04702] [EC:2.7.11.1]

101058316

RUNX1; runt-related transcription factor 1 isoform X1 [KO:K08367]

462187

CSF1R; macrophage colony-stimulating factor 1 receptor isoform X1 [KO:K05090] [EC:2.7.10.1]

748680

MPO; myeloperoxidase isoform X2 [KO:K10789] [EC:1.11.2.2]

471627

CSF2; granulocyte-macrophage colony-stimulating factor [KO:K05427]

471626

IL3; interleukin-3 precursor [KO:K04736]

472816

RUNX1T1; protein CBFA2T1 isoform X2 [KO:K10053]

453736

PML; protein PML [KO:K10054] [EC:2.3.2.-]

454647

RARA; retinoic acid receptor alpha isoform X1 [KO:K08527]

100614588

ZBTB16; zinc finger and BTB domain-containing protein 16 isoform X1 [KO:K10055]

746673

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

460057

PER2; period circadian protein homolog 2 isoform X1 [KO:K02633]

451169

SPI1; transcription factor PU.1 isoform X1 [KO:K09438]

462118

CD14; monocyte differentiation antigen CD14 precursor [KO:K04391]

454069

ITGAM; integrin alpha-M precursor [KO:K06461]

457259

high affinity immunoglobulin gamma Fc receptor I isoform X2 [KO:K06498]

743538

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

100610077

BCL2A1; bcl-2-related protein A1 isoform X1 [KO:K02162]

467260

CCNA1; cyclin-A1 [KO:K06627]

461467

CCNA2; cyclin-A2 [KO:K06627]

464393

MYC; myc proto-oncogene protein [KO:K04377]

452115

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

454667

JUP; junction plakoglobin isoform X1 [KO:K10056]

745839

TCF7; LOW QUALITY PROTEIN: transcription factor 7 [KO:K02620]

744526

TCF7L1; transcription factor 7-like 1 isoform X2 [KO:K04490]

450743

TCF7L2; transcription factor 7-like 2 isoform X1 [KO:K04491]

461425

LEF1; lymphoid enhancer-binding factor 1 isoform X5 [KO:K04492]

747442

CCND1; G1/S-specific cyclin-D1 [KO:K04503]

463188

PPARD; peroxisome proliferator-activated receptor delta isoform X6 [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)