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.

Human Diseases; Cancer: specific types
BRITE hierarchy

Capra hircus (goat) [GN:chx]

PMID:16236521

Steffen B, Muller-Tidow C, Schwable J, Berdel WE, Serve H.

The molecular pathogenesis of acute myeloid leukemia.

Crit Rev Oncol Hematol 56:195-221 (2005)
DOI:10.1016/j.critrevonc.2004.10.012

PMID:12563308

Tenen DG.

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

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

PMID:16146838

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

Signal transduction of oncogenic Flt3.

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

PMID:12951584

Stirewalt DL, Radich JP.

The role of FLT3 in haematopoietic malignancies.

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

PMID:16642045

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

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

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

PMID:15625120

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

Normal and oncogenic forms of the receptor tyrosine kinase kit.

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

PMID:11721960

Lorsbach RB, Downing JR.

The role of the AML1 transcription factor in leukemogenesis.

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

PMID:12468433

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.

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

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

PMID:16352814

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

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

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

PMID:12529654

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

New mechanisms of AML1 gene alteration in hematological malignancies.

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

PMID:12032780

Scandura JM, Boccuni P, Cammenga J, Nimer SD

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

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

PMID:10717473

Lutterbach B, Hiebert SW

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

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

PMID:19075268

Koschmieder S, Halmos B, Levantini E, Tenen DG

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

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

PMID:15985538

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

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

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

PMID:12130514

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

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

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

PMID:12393465

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

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

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

PMID:15024077

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

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

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

PMID:11090075

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

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

Blood 96:3894-9 (2000)

PMID:15160934

Jing Y

The PML-RARalpha fusion protein and targeted therapy for acute promyelocytic leukemia.

Leuk Lymphoma 45:639-48 (2004)
DOI:10.1080/10428190310001609933

PMID:11607818

Alcalay M, Orleth A, Sebastiani C, Meani N, Chiaradonna F, Casciari C, Sciurpi MT, Gelmetti V, Riganelli D, Minucci S, Fagioli M, Pelicci PG

Common themes in the pathogenesis of acute myeloid leukemia.

Oncogene 20:5680-94 (2001)
DOI:10.1038/sj.onc.1204642

PMID:19855079

Rice KL, Hormaeche I, Doulatov S, Flatow JM, Grimwade D, Mills KI, Leiva M, Ablain J, Ambardekar C, McConnell MJ, Dick JE, Licht JD

Comprehensive genomic screens identify a role for PLZF-RARalpha as a positive regulator of cell proliferation via direct regulation of c-MYC.

Blood 114:5499-511 (2009)
DOI:10.1182/blood-2009-03-206524

PMID:17554387

Mikesch JH, Steffen B, Berdel WE, Serve H, Muller-Tidow C.

The emerging role of Wnt signaling in the pathogenesis of acute myeloid leukemia.

Leukemia 21:1638-47 (2007)
DOI:10.1038/sj.leu.2404732