Defining niche interactions to target chronic myeloid leukemia stem cells

Targeting Abnormal Hematopoietic Stem Cells in Chronic Myeloid Leukemia and Philadelphia Chromosome-Negative Classical Myeloproliferative Neoplasms

“…Normal HSCs interact with endothelial cells, neural cells, osteoclasts, mesenchymal stromal cells and osteoblasts in the BMM [ 17 , 25 , 152 , 153 ]. Selectins, integrins, and CD44 expressions are required for HSC engraftment and adhesion between fibronectin on the extracellular matrix and CD106 (VCAM-I) on the BM endothelium [ 23 , 25 , 152 , 153 , 154 ].…”

“…Normal HSCs interact with endothelial cells, neural cells, osteoclasts, mesenchymal stromal cells and osteoblasts in the BMM [ 17 , 25 , 152 , 153 ]. Selectins, integrins, and CD44 expressions are required for HSC engraftment and adhesion between fibronectin on the extracellular matrix and CD106 (VCAM-I) on the BM endothelium [ 23 , 25 , 152 , 153 , 154 ]. HSC rolling and homing is mediated by interaction between constitutively expressed E- and P- selectins and VLA4, where SDF1 and its receptor CXCR4 acts as a chemo-attractant through β1/2− integrins and SDF1 for stable engraftment [ 23 , 25 , 152 , 153 , 154 , 155 , 156 ].…”

“…Selectins, integrins, and CD44 expressions are required for HSC engraftment and adhesion between fibronectin on the extracellular matrix and CD106 (VCAM-I) on the BM endothelium [ 23 , 25 , 152 , 153 , 154 ]. HSC rolling and homing is mediated by interaction between constitutively expressed E- and P- selectins and VLA4, where SDF1 and its receptor CXCR4 acts as a chemo-attractant through β1/2− integrins and SDF1 for stable engraftment [ 23 , 25 , 152 , 153 , 154 , 155 , 156 ]. BCR-ABL1 impairs the SDF1/CXCR4 axis in normal HSCs but upregulates it in CML stem cells, conferring selective homing and survival in the BM niche [ 17 , 23 , 152 , 153 , 157 , 158 ].…”

“…HSC rolling and homing is mediated by interaction between constitutively expressed E- and P- selectins and VLA4, where SDF1 and its receptor CXCR4 acts as a chemo-attractant through β1/2− integrins and SDF1 for stable engraftment [ 23 , 25 , 152 , 153 , 154 , 155 , 156 ]. BCR-ABL1 impairs the SDF1/CXCR4 axis in normal HSCs but upregulates it in CML stem cells, conferring selective homing and survival in the BM niche [ 17 , 23 , 152 , 153 , 157 , 158 ]. In addition, CML stem cells have defective β1-integrin levels (VLA4 or VLA5), allowing redistribution and mobilization into the PB and other organs, e.g., spleen with the potential of uncontrolled extramedullary myeloproliferation and local LSC reservoirs [ 152 , 154 , 157 ].…”

“…BCR-ABL1 impairs the SDF1/CXCR4 axis in normal HSCs but upregulates it in CML stem cells, conferring selective homing and survival in the BM niche [ 17 , 23 , 152 , 153 , 157 , 158 ]. In addition, CML stem cells have defective β1-integrin levels (VLA4 or VLA5), allowing redistribution and mobilization into the PB and other organs, e.g., spleen with the potential of uncontrolled extramedullary myeloproliferation and local LSC reservoirs [ 152 , 154 , 157 ]. CML stem cells alter extrinsic factors and upregulate expression of CD44 + and E-selectin to promote prominent BMM changes such as marrow fibrosis for exclusive stem cell engraftment and dormancy, offering protection from drug-targeting [ 25 , 152 , 154 , 158 , 159 , 160 , 161 , 162 ].…”