Contributions
Abstract: EP664
Type: E-Poster Presentation
Session title: Chronic myeloid leukemia - Biology & Translational Research
Background
Recent data suggest that the disease-related microenvironment (stem cell niche) is critically involved in drug resistance of leukemic stem cells (LSC) in chronic myeloid leukemia (CML). Attacking the stem cell niche in CML may thus be an effective approach to overcome LSC resistance. We have recently shown that osteoblasts induce substantial LSC resistance against tyrosine kinase inhibitors (TKI) in CML. We also found that several BCR-ABL1 TKI, like ponatinib or nilotinib, exert growth-inhibitory effects on endothelial cells.
Aims
In the current study, we screened for drugs that are able to suppress the growth and viability of osteoblasts and endothelial cells in the CML context.
Methods
Proliferation was analyzed by measuring 3H-thymidine uptake in niche-related cells and apoptosis was measured by AnnexinV/DAPI-staining.
Results
We found that PI3K/mTOR blocker BEZ235 and pan-PI3K inhibitor copanlisib suppress growth and viability of primary osteoblasts (BEZ235 IC50: 0.05 µM, copanlisib IC50: 0.05 µM), the osteoblastic cell line CAL-72 (BEZ235 IC50: 0.5 µM; copanlisib IC50: 1 µM), primary umbilical vein-derived endothelial cells (BEZ235 IC50: 0.5 µM; copanlisib IC50: 0.5 µM), and the endothelial cell line HMEC-1 (BEZ235 IC50: 1 µM; copanlisib IC50: 1 µM). Moreover, we found that BEZ235 and copanlisib cooperate with nilotinib and ponatinib in suppressing growth and viability of osteoblasts and endothelial cells. Finally, BEZ235 and copanlisib were found to overcome osteoblast-induced resistance of K562 cells, KU812 cells, and primary CD34+/CD38− CML LSC against nilotinib and ponatinib.
Conclusion
Together our data suggest that targeting niche cells by BEZ235 and copanlisib is an effective approach to overcome niche-induced TKI resistance in CML.
Keyword(s): BCR-ABL, PI3K, Stem cell niche
Abstract: EP664
Type: E-Poster Presentation
Session title: Chronic myeloid leukemia - Biology & Translational Research
Background
Recent data suggest that the disease-related microenvironment (stem cell niche) is critically involved in drug resistance of leukemic stem cells (LSC) in chronic myeloid leukemia (CML). Attacking the stem cell niche in CML may thus be an effective approach to overcome LSC resistance. We have recently shown that osteoblasts induce substantial LSC resistance against tyrosine kinase inhibitors (TKI) in CML. We also found that several BCR-ABL1 TKI, like ponatinib or nilotinib, exert growth-inhibitory effects on endothelial cells.
Aims
In the current study, we screened for drugs that are able to suppress the growth and viability of osteoblasts and endothelial cells in the CML context.
Methods
Proliferation was analyzed by measuring 3H-thymidine uptake in niche-related cells and apoptosis was measured by AnnexinV/DAPI-staining.
Results
We found that PI3K/mTOR blocker BEZ235 and pan-PI3K inhibitor copanlisib suppress growth and viability of primary osteoblasts (BEZ235 IC50: 0.05 µM, copanlisib IC50: 0.05 µM), the osteoblastic cell line CAL-72 (BEZ235 IC50: 0.5 µM; copanlisib IC50: 1 µM), primary umbilical vein-derived endothelial cells (BEZ235 IC50: 0.5 µM; copanlisib IC50: 0.5 µM), and the endothelial cell line HMEC-1 (BEZ235 IC50: 1 µM; copanlisib IC50: 1 µM). Moreover, we found that BEZ235 and copanlisib cooperate with nilotinib and ponatinib in suppressing growth and viability of osteoblasts and endothelial cells. Finally, BEZ235 and copanlisib were found to overcome osteoblast-induced resistance of K562 cells, KU812 cells, and primary CD34+/CD38− CML LSC against nilotinib and ponatinib.
Conclusion
Together our data suggest that targeting niche cells by BEZ235 and copanlisib is an effective approach to overcome niche-induced TKI resistance in CML.
Keyword(s): BCR-ABL, PI3K, Stem cell niche