KEGG PATHWAY: mmu05221

PATHWAY: mmu05221

Entry

mmu05221                    Pathway

Name

Acute myeloid leukemia - Mus musculus (house mouse)

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

mmu05221

Acute myeloid leukemia

Organism

Mus musculus (house mouse) [GN:mmu]

Gene

16590

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

14255

Flt3; FMS-like tyrosine kinase 3 [KO:K05092] [EC:2.7.10.1]

18706

Pik3ca; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [KO:K00922] [EC:2.7.1.153]

18707

Pik3cd; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [KO:K00922] [EC:2.7.1.153]

74769

Pik3cb; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [KO:K00922] [EC:2.7.1.153]

18709

Pik3r2; phosphoinositide-3-kinase regulatory subunit 2 [KO:K02649]

18708

Pik3r1; phosphoinositide-3-kinase regulatory subunit 1 [KO:K02649]

18710

Pik3r3; phosphoinositide-3-kinase regulatory subunit 3 [KO:K02649]

11651

Akt1; thymoma viral proto-oncogene 1 [KO:K04456] [EC:2.7.11.1]

11652

Akt2; thymoma viral proto-oncogene 2 [KO:K04456] [EC:2.7.11.1]

23797

Akt3; thymoma viral proto-oncogene 3 [KO:K04456] [EC:2.7.11.1]

12675

Chuk; conserved helix-loop-helix ubiquitous kinase [KO:K04467] [EC:2.7.11.10]

16150

Ikbkb; inhibitor of kappaB kinase beta [KO:K07209] [EC:2.7.11.10]

16151

Ikbkg; inhibitor of kappaB kinase gamma [KO:K07210]

18033

Nfkb1; nuclear factor of kappa light polypeptide gene enhancer in B cells 1, p105 [KO:K02580]

19697

Rela; v-rel reticuloendotheliosis viral oncogene homolog A (avian) [KO:K04735]

12015

Bad; BCL2-associated agonist of cell death [KO:K02158]

56717

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

13685

Eif4ebp1; eukaryotic translation initiation factor 4E binding protein 1 [KO:K07205]

58988

Rps6kb2; ribosomal protein S6 kinase, polypeptide 2 [KO:K04688] [EC:2.7.11.1]

72508

Rps6kb1; ribosomal protein S6 kinase, polypeptide 1 [KO:K04688] [EC:2.7.11.1]

14784

Grb2; growth factor receptor bound protein 2 [KO:K04364]

20662

Sos1; SOS Ras/Rac guanine nucleotide exchange factor 1 [KO:K03099]

20663

Sos2; SOS Ras/Rho guanine nucleotide exchange factor 2 [KO:K03099]

15461

Hras; Harvey rat sarcoma virus oncogene [KO:K02833]

18176

Nras; neuroblastoma ras oncogene [KO:K07828]

16653

Kras; Kirsten rat sarcoma viral oncogene homolog [KO:K07827]

11836

Araf; Araf proto-oncogene, serine/threonine kinase [KO:K08845] [EC:2.7.11.1]

109880

Braf; Braf transforming gene [KO:K04365] [EC:2.7.11.1]

110157

Raf1; v-raf-leukemia viral oncogene 1 [KO:K04366] [EC:2.7.11.1]

26395

Map2k1; mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]

26396

Map2k2; mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]

26413

Mapk1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]

26417

Mapk3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]

20848

Stat3; signal transducer and activator of transcription 3 [KO:K04692]

20850

Stat5a; signal transducer and activator of transcription 5A [KO:K11223]

20851

Stat5b; signal transducer and activator of transcription 5B [KO:K11224]

18712

Pim1; proviral integration site 1 [KO:K04702] [EC:2.7.11.1]

18715

Pim2; proviral integration site 2 [KO:K08806] [EC:2.7.11.1]

12394

Runx1; runt related transcription factor 1 [KO:K08367]

12978

Csf1r; colony stimulating factor 1 receptor [KO:K05090] [EC:2.7.10.1]

17523

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

12981

Csf2; colony stimulating factor 2 (granulocyte-macrophage) [KO:K05427]

16187

Il3; interleukin 3 [KO:K04736]

12395

Runx1t1; RUNX1 translocation partner 1 [KO:K10053]

18854

Pml; promyelocytic leukemia [KO:K10054] [EC:2.3.2.-]

19401

Rara; retinoic acid receptor, alpha [KO:K08527]

235320

Zbtb16; zinc finger and BTB domain containing 16 [KO:K10055]

12606

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

18627

Per2; period circadian clock 2 [KO:K02633]

20375

Spi1; Spi-1 proto-oncogene [KO:K09438]

12475

Cd14; CD14 antigen [KO:K04391]

16409

Itgam; integrin alpha M [KO:K06461]

14129

Fcgr1; Fc receptor, IgG, high affinity I [KO:K06498]

110794

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

12047

Bcl2a1d; B cell leukemia/lymphoma 2 related protein A1d [KO:K02162]

12044

Bcl2a1a; B cell leukemia/lymphoma 2 related protein A1a [KO:K02162]

12045

Bcl2a1b; B cell leukemia/lymphoma 2 related protein A1b [KO:K02162]

12046

Bcl2a1c; B cell leukemia/lymphoma 2 related protein A1c [KO:K02162]

12428

Ccna2; cyclin A2 [KO:K06627]

12427

Ccna1; cyclin A1 [KO:K06627]

17869

Myc; myelocytomatosis oncogene [KO:K04377]

67603

Dusp6; dual specificity phosphatase 6 [KO:K21946] [EC:3.1.3.16 3.1.3.48]

16480

Jup; junction plakoglobin [KO:K10056]

21414

Tcf7; transcription factor 7, T cell specific [KO:K02620]

21415

Tcf7l1; transcription factor 7 like 1 (T cell specific, HMG box) [KO:K04490]

21416

Tcf7l2; transcription factor 7 like 2, T cell specific, HMG box [KO:K04491]

16842

Lef1; lymphoid enhancer binding factor 1 [KO:K04492]

12443

Ccnd1; cyclin D1 [KO:K04503]

19015

Ppard; peroxisome proliferator activator 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)