Table 3.

Concepts for targeted therapy for diverse subentities of acute myeloid leukemia (AML).

Target/AML SubentityCompoundMechanism
PML-RARA in acute promyelocytic leukemia with the t(15;17)(q22;q21) All-trans retinoic acid (ATRA) 

  • - Suppression of the differentiation stop mediated by the PML-RARA fusion

  • - Induction of differentiation

 
 Arsenic trioxide (AS2O3) 

  • - Degradation of the fusion protein encoded by the PML-RARA oncogene

  • - Induction of differentiation

 
FLT3 mutated AML Unspecific FLT3-inhibitors:

  • - indoline tyrosine kinase inhibitors (SU5416; sunitinib - SU11248)

  • - small molecular compounds: PKC412Specific FLT3-inhibition:

  • - tandutinib (MLN518), CEP701

 

  • - Inhibition of downstream signaling via MAPK and STAT pathways

  • - Reduction of cellular proliferation

  • - Increase of apoptosis

  • - Induction of cell cycle arrest

 
CD117- positive or KIT-mutated AML Imatinib 

  • - Prevention of autophosphorylation of the c-KIT receptor tyrosine kinase

 
KIT mutations in CBF leukemias (RUNX1/RUNX1T1 ; CBFB-MYH11) Dasatinib 

  • - Activation of downstream signaling via MAPK and Akt pathways

 
Constitutive activation of MAPK (Mitogen-activated protein kinase) signaling, e.g., in RAS mutated AML Farnesyltransferase inhibitors:

  • - tipifarnib (R1157777)

  • - lonafarnib

 

  • - Inhibition of farnesyl transferases

  • - Inhibition of Ras binding to the cell membrane

  • - Induction of apoptosis

  • - Inhibition of anchorage-independent growth

 
DNA hypermethylation Demethylating agents:

  • - 5-azacytidine

  • - decitabine (5-aza-2′-deoxycytidine)

 

  • - Reduction of hypermethylation

  • - Reexpression of tumor suppressor genes

 
Deacetylase activity Histone deacetylase (HDAC) inhibitors:

  • - valproic acid

 

  • - Induction of histone hyperacetylation

  • - Induction of apoptosis and differentiation

  • - Downregulation of c-MYC expression

 
NPM1 mutated/FLT3wt AML without adverse chromosomal abnormalities ATRA (in addition to cytotoxic therapy) 

  • - remains to be determined

 
Target/AML SubentityCompoundMechanism
PML-RARA in acute promyelocytic leukemia with the t(15;17)(q22;q21) All-trans retinoic acid (ATRA) 

  • - Suppression of the differentiation stop mediated by the PML-RARA fusion

  • - Induction of differentiation

 
 Arsenic trioxide (AS2O3) 

  • - Degradation of the fusion protein encoded by the PML-RARA oncogene

  • - Induction of differentiation

 
FLT3 mutated AML Unspecific FLT3-inhibitors:

  • - indoline tyrosine kinase inhibitors (SU5416; sunitinib - SU11248)

  • - small molecular compounds: PKC412Specific FLT3-inhibition:

  • - tandutinib (MLN518), CEP701

 

  • - Inhibition of downstream signaling via MAPK and STAT pathways

  • - Reduction of cellular proliferation

  • - Increase of apoptosis

  • - Induction of cell cycle arrest

 
CD117- positive or KIT-mutated AML Imatinib 

  • - Prevention of autophosphorylation of the c-KIT receptor tyrosine kinase

 
KIT mutations in CBF leukemias (RUNX1/RUNX1T1 ; CBFB-MYH11) Dasatinib 

  • - Activation of downstream signaling via MAPK and Akt pathways

 
Constitutive activation of MAPK (Mitogen-activated protein kinase) signaling, e.g., in RAS mutated AML Farnesyltransferase inhibitors:

  • - tipifarnib (R1157777)

  • - lonafarnib

 

  • - Inhibition of farnesyl transferases

  • - Inhibition of Ras binding to the cell membrane

  • - Induction of apoptosis

  • - Inhibition of anchorage-independent growth

 
DNA hypermethylation Demethylating agents:

  • - 5-azacytidine

  • - decitabine (5-aza-2′-deoxycytidine)

 

  • - Reduction of hypermethylation

  • - Reexpression of tumor suppressor genes

 
Deacetylase activity Histone deacetylase (HDAC) inhibitors:

  • - valproic acid

 

  • - Induction of histone hyperacetylation

  • - Induction of apoptosis and differentiation

  • - Downregulation of c-MYC expression

 
NPM1 mutated/FLT3wt AML without adverse chromosomal abnormalities ATRA (in addition to cytotoxic therapy) 

  • - remains to be determined

 
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