Candidate therapeutic targets implicated in CP CML LSC/BMM interactions
| Target or survival factor . | Pathway . | Exemplar inhibitors/activators . | Reference . | CML clinical trial . |
|---|---|---|---|---|
| β1-integrins | Cell adhesion; proliferation | IFN-α | 87 | Yes |
| 86 | ||||
| CD26 | CXCL12/CXCR4 signaling | Gliptins | 90 | No |
| CD44 | E-selectin ligands; homing, engraftment | NA | 83 | No |
| CXCR4 | CXCL12/CXCR4 axis | AMD3465; AMD3100; plerixafor | 123 | Yes |
| 124 | ||||
| 125 | ||||
| 126 | ||||
| BMP2/4 | BMP signaling | NA | 127 | No |
| Galectin-3 | BM lodgement | NA | 85 | No |
| HIF1α | Hypoxia response | NA | 128, 129 | No |
| IFN-α | Immune surveillance; cytokine-mediated proliferation | Interferon alfa-2a | 130 | Yes |
| 131 | ||||
| 132 | ||||
| 133 | ||||
| 134 | ||||
| IL-1RAP/IL-1 | NFKβ/AKT signaling | IL-1RAP mAb (mAb81.2) | 110 | Yes |
| 135 | ||||
| 136 | ||||
| IL-6 | IL-6Rα signaling from the microenvironment | αIL-6 mAb | 92 | No |
| LYN | CXCR4/CXCL12 signaling in lipid rafts | Methyl-β-cyclodextrin; PP2 | 89 | No |
| MHC-II/CIITA | JAK/STAT signaling | Ruxolitinib, IFN-γ | 97 | Yes |
| miR-126 | Exosomal transfer | 2-O-Me-miR-126 | 137 | No |
| N-cadherins | N-cadherin/Wnt/β-catenin signaling | ICG001 | 88 | No |
| JAGGED-1 | NOTCH signaling | NA | 138 | No |
| MPL | JAK/STAT signaling; engraftment | NA | 139 | No |
| PD-1/PD-L1 | Immune surveillance | αPD-L1 mAb | 95, 96 | Yes |
| αPD-1 mAb | ||||
| PIGF | VEGF signaling: BM angiogenesis; proliferation; metabolism | 5D11D4 | 140 | No |
| Selectins | BM homing; engraftment | GMI-1271 | 84, 141 | No |
| TGF-β1 | Osteoblast → LSC TGF-β signaling | Parathyroid hormone | 142 | No |
| Target or survival factor . | Pathway . | Exemplar inhibitors/activators . | Reference . | CML clinical trial . |
|---|---|---|---|---|
| β1-integrins | Cell adhesion; proliferation | IFN-α | 87 | Yes |
| 86 | ||||
| CD26 | CXCL12/CXCR4 signaling | Gliptins | 90 | No |
| CD44 | E-selectin ligands; homing, engraftment | NA | 83 | No |
| CXCR4 | CXCL12/CXCR4 axis | AMD3465; AMD3100; plerixafor | 123 | Yes |
| 124 | ||||
| 125 | ||||
| 126 | ||||
| BMP2/4 | BMP signaling | NA | 127 | No |
| Galectin-3 | BM lodgement | NA | 85 | No |
| HIF1α | Hypoxia response | NA | 128, 129 | No |
| IFN-α | Immune surveillance; cytokine-mediated proliferation | Interferon alfa-2a | 130 | Yes |
| 131 | ||||
| 132 | ||||
| 133 | ||||
| 134 | ||||
| IL-1RAP/IL-1 | NFKβ/AKT signaling | IL-1RAP mAb (mAb81.2) | 110 | Yes |
| 135 | ||||
| 136 | ||||
| IL-6 | IL-6Rα signaling from the microenvironment | αIL-6 mAb | 92 | No |
| LYN | CXCR4/CXCL12 signaling in lipid rafts | Methyl-β-cyclodextrin; PP2 | 89 | No |
| MHC-II/CIITA | JAK/STAT signaling | Ruxolitinib, IFN-γ | 97 | Yes |
| miR-126 | Exosomal transfer | 2-O-Me-miR-126 | 137 | No |
| N-cadherins | N-cadherin/Wnt/β-catenin signaling | ICG001 | 88 | No |
| JAGGED-1 | NOTCH signaling | NA | 138 | No |
| MPL | JAK/STAT signaling; engraftment | NA | 139 | No |
| PD-1/PD-L1 | Immune surveillance | αPD-L1 mAb | 95, 96 | Yes |
| αPD-1 mAb | ||||
| PIGF | VEGF signaling: BM angiogenesis; proliferation; metabolism | 5D11D4 | 140 | No |
| Selectins | BM homing; engraftment | GMI-1271 | 84, 141 | No |
| TGF-β1 | Osteoblast → LSC TGF-β signaling | Parathyroid hormone | 142 | No |
Column 1 indicates key survival factors that act through LSC/BMM interactions. Column 2 shows the roles of these survival factors in cellular pathways (if known or as proposed by investigators). Column 3 lists exemplar compounds that have been identified as having potential therapeutic value for each target (if known). Column 4 provides the references in which the targets were described. Column 5 indicates whether targets or compounds have been evaluated in clinical trials.
miR, microRNA; NA, not applicable; VEGF, vascular endothelial growth factor.