Two major types of genetic event are crucial for the molecular pathogenesis of acute myeloid leukemias (AML): activating mutations of signal transduction intermediates and alterations in myeloid transcription factors governing hematopoietic differentiation. Both aberrant and constitutive activation of signal transduction molecules are found in about 50% of primary AML bone marrow samples, and seem to contribute to the increased proliferation and apoptosis resistance. The most common of these activating events were observed in the FLT3, in N-Ras and K-Ras and in Kit. Specific haematopoietic transcription factors are crucial for differentiation to particular lineages during normal differentiation, but are frequently disrupted in AML. Some mechanisms of disruption involve the effect of fusion proteins that are generated by chromosomal translocations on haematopoietic transcription factors. In other cases, the transcription factors themselves are mutated.

Acute Myeloid LeukemiaSignaling Pathway

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18696-1-AP

ELISA, WB, IHC

HRAS (Ras)

18295-1-AP

Rabbit poly

ELISA, WB, IHC

S6K1 / p70(S6K) 14485-1-AP Rabbit poly ELISA, WB, IHC

65030-1-Ig

Mouse mono

ELISA, WB, IHC

PIP3

CellSurvival

ProteinSynthesis

Block of differentiation

Anti-apoptotic genes

DNA

Proliferation

DNA

DNA DNA

DNA

DNA

DNA

DNA

Jak-STATSignaling

AML 1targetsgenes

C/EBPαtargetgenes

PU.1targetgenes

Anti-apoptosis

Genetic alterations

Oncogenes:c-KIT, FLT3, N- or K-Ras, AML1-ETO, PML-RARα, PLZF-RARα

Tumor suppressors:AML1, C/EBPα, PU.1

Hematopoietic progenitors

Acute myeloblastic leukemia with minimal differentiation (MO)

Acute myeloblastic leukemia without maturation (M1)

Acute myeloblastic leukemia with maturation (M2)

Acute promyelocytic leukemia (M3)

Acute myelomonocytic leukemia(M4)

Acute myelomonocytic leuke-mia with abnormal eosinophils (M4Eo)

Acute monocytic leukemia (M5)

Erythroleukemia (M6)

Acute megakaryocytic leuke-mia (M7)

Hematopoieticcell lineage

mTOR

c-Myc

10828-1-AP

Rabbit poly

ELISA, WB, IHC

4EBP1 / EIF4EBP1

c-KIT

Rabbit poly

JUP

11146-1-AP

Rabbit poly

ELISA, WB, IHC

STAT3

51076-2-AP

Rabbit poly

ELISA, WB, IHC