KEGG PATHWAY: bbub05221

PATHWAY: bbub05221

Entry

bbub05221                   Pathway

Name

Acute myeloid leukemia - Bubalus bubalis (water buffalo)

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

bbub05221

Acute myeloid leukemia

Organism

Bubalus bubalis (water buffalo) [GN:bbub]

Gene

102410945

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

102402092

FLT3; receptor-type tyrosine-protein kinase FLT3 isoform X1 [KO:K05092] [EC:2.7.10.1]

102404165

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

102400519

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

102404610

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

102415109

PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]

102404517

PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta isoform X1 [KO:K02649]

102395384

phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]

102397969

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

102398761

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

102391021

AKT3; RAC-gamma serine/threonine-protein kinase isoform X4 [KO:K04456] [EC:2.7.11.1]

102399613

CHUK; inhibitor of nuclear factor kappa-B kinase subunit alpha isoform X3 [KO:K04467] [EC:2.7.11.10]

102398886

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

102394706

IKBKG; NF-kappa-B essential modulator isoform X6 [KO:K07210]

102403930

NFKB1; nuclear factor NF-kappa-B p105 subunit isoform X2 [KO:K02580]

102397938

RELA; transcription factor P65 [KO:K04735]

102414298

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

102407977

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

112582961

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

102402840

RPS6KB1; ribosomal protein S6 kinase beta-1 isoform X4 [KO:K04688] [EC:2.7.11.1]

102413442

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

102394713

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

102412823

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

102392913

SOS1; son of sevenless homolog 1 isoform X3 [KO:K03099]

112587129

GTPase HRas-like [KO:K02833]

102399487

NRAS; GTPase NRas isoform X2 [KO:K07828]

102392995

KRAS; GTPase KRas isoform X2 [KO:K07827]

102392863

ARAF; serine/threonine-protein kinase A-Raf isoform X2 [KO:K08845] [EC:2.7.11.1]

102401079

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

102412922

RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]

102396842

MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 isoform X1 [KO:K04368] [EC:2.7.12.2]

102401744

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

102396206

MAPK1; mitogen-activated protein kinase 1 isoform X1 [KO:K04371] [EC:2.7.11.24]

102403296

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

102414888

STAT3; signal transducer and activator of transcription 3 isoform X1 [KO:K04692]

102415442

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

102400858

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

102395299

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

102408117

PIM2; serine/threonine-protein kinase pim-2 [KO:K08806] [EC:2.7.11.1]

102392702

RUNX1; runt-related transcription factor 1 isoform X4 [KO:K08367]

102414145

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

102404921

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

102413568

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

102413882

IL3; interleukin-3 precursor [KO:K04736]

102390205

RUNX1T1; protein CBFA2T1 isoform X3 [KO:K10053]

102394614

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

102412210

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

102399156

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

102410413

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

102407269

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

102398044

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

102399257

CD14; monocyte differentiation antigen CD14 isoform X1 [KO:K04391]

102396526

integrin alpha-M [KO:K06461]

102410120

FCGR1A; LOW QUALITY PROTEIN: high affinity immunoglobulin gamma Fc receptor I [KO:K06498]

102402846

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

102395403

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

102398715

CCNA2; cyclin-A2 [KO:K06627]

102408087

CCNA1; cyclin-A1 [KO:K06627]

102402664

MYC; myc proto-oncogene protein isoform X1 [KO:K04377]

102391799

DUSP6; dual specificity protein phosphatase 6 isoform X1 [KO:K21946] [EC:3.1.3.16 3.1.3.48]

102395630

junction plakoglobin [KO:K10056]

102408996

TCF7; transcription factor 7 isoform X2 [KO:K02620]

102410081

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

102393101

TCF7L2; transcription factor 7-like 2 isoform X10 [KO:K04491]

102409520

LEF1; lymphoid enhancer-binding factor 1 isoform X1 [KO:K04492]

102411133

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

102390490

PPARD; peroxisome proliferator-activated receptor delta isoform X1 [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)