Table 1.

Candidate therapeutic targets in CP CML LSCs

Target or survival factorPathwayExemplar inhibitors/activatorsReferenceCML clinical trial
ALOX15 β-catenin; PI3K/AKT signaling PD146176 106  No 
ALOX5 Wnt/β-catenin signaling Zileuton 69  Yes 
Autophagy Autophagy Chloroquine; bafilomycin A1 113  Yes 
As2O3 
 114  
 115  
BCL6 PI3K/AKT/FOX3a/BCL6 signaling RI-BPI 56  No 
BLK MYC/PAX5/BLK/CDKN1B signaling NA 116  No 
CCN Wnt/Ca2+/NFAT signaling Cyclosporin A 68  No 
CD25 JAK/STAT signaling BEZ235 111  No 
CD70/CD27 Wnt/β-catenin signaling αCD70 mAb 67  No 
c-MYC and TP53 apoptosis CPI-203; RITA/RG7388 98  No 
EZH2 Histone H3 K27 trimethylation GSK 343; GSK126 101  No 
EPZ-6438 (tazemetostat) 100  
Farnesyl transferases RAS signaling; protein farnesylation BMS-214662 117  Yes 
FOX03A TGF-β/AKT/FOXO3a/BCL6 signaling NA 57  No 
58  
GSK3β Wnt/β-catenin signaling SB216763 118  No 
HDACs Histone acetylation LBH589 119  Yes 
JAK2 JAK/STAT signaling Ruxolitinib 74  Yes 
PML Apoptosis; mTOR repression As2O3 120  Yes 
PP2A JAK/STAT/β-catenin signaling 1,9-dideoxy-forskolin; FTY720 76  No 
77  
PPARγ STAT5/HIF2α/CITED2 Pioglitazone 102  Yes 
103  
RAD52 DNA repair RAD52 F79 peptide aptamer 82  No 
SIRT1 Deacetylation of p53 Tenovin-6 121  No 
SMO Hedgehog signaling Cyclopamine; LDE225 60  Yes 
61  
62  
STAT3 JAK/STAT signaling BP-5087 80  No 
TGF-β RI, ALK5 TGF-β/AKT/FOXO3a/BCL6 signaling Ly364947; EW-7197 58  No 
122  
Target or survival factorPathwayExemplar inhibitors/activatorsReferenceCML clinical trial
ALOX15 β-catenin; PI3K/AKT signaling PD146176 106  No 
ALOX5 Wnt/β-catenin signaling Zileuton 69  Yes 
Autophagy Autophagy Chloroquine; bafilomycin A1 113  Yes 
As2O3 
 114  
 115  
BCL6 PI3K/AKT/FOX3a/BCL6 signaling RI-BPI 56  No 
BLK MYC/PAX5/BLK/CDKN1B signaling NA 116  No 
CCN Wnt/Ca2+/NFAT signaling Cyclosporin A 68  No 
CD25 JAK/STAT signaling BEZ235 111  No 
CD70/CD27 Wnt/β-catenin signaling αCD70 mAb 67  No 
c-MYC and TP53 apoptosis CPI-203; RITA/RG7388 98  No 
EZH2 Histone H3 K27 trimethylation GSK 343; GSK126 101  No 
EPZ-6438 (tazemetostat) 100  
Farnesyl transferases RAS signaling; protein farnesylation BMS-214662 117  Yes 
FOX03A TGF-β/AKT/FOXO3a/BCL6 signaling NA 57  No 
58  
GSK3β Wnt/β-catenin signaling SB216763 118  No 
HDACs Histone acetylation LBH589 119  Yes 
JAK2 JAK/STAT signaling Ruxolitinib 74  Yes 
PML Apoptosis; mTOR repression As2O3 120  Yes 
PP2A JAK/STAT/β-catenin signaling 1,9-dideoxy-forskolin; FTY720 76  No 
77  
PPARγ STAT5/HIF2α/CITED2 Pioglitazone 102  Yes 
103  
RAD52 DNA repair RAD52 F79 peptide aptamer 82  No 
SIRT1 Deacetylation of p53 Tenovin-6 121  No 
SMO Hedgehog signaling Cyclopamine; LDE225 60  Yes 
61  
62  
STAT3 JAK/STAT signaling BP-5087 80  No 
TGF-β RI, ALK5 TGF-β/AKT/FOXO3a/BCL6 signaling Ly364947; EW-7197 58  No 
122  

Column 1 indicates key survival factors/drug targets intrinsic to the LSC. Column 2 lists the roles of these factors/targets in cellular pathways (if known or as proposed by investigators). Column 3 shows exemplar compounds that have been identified as having potential therapeutic value for each factor/target or pathway (if known). Column 4 provides the references in which the factors/targets are described. Column 5 indicates whether factors/targets or compounds have been evaluated in clinical trials.

As2O3, arsenic trioxide; NA, not available.

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