FBXO3-mediated DUSP9 ubiquitination promotes leukemia stem cell maintenance and tyrosine kinase inhibitor resistance in chronic myeloid leukemia - PubMed
3 hours ago
- #TKI resistance
- #CML-LSCs
- #FBXO3
- FBXO3 is highly upregulated in CD34+ CML stem cells from TKI-resistant patients and identified as a novel CML-LSC marker.
- FBXO3 deficiency induces apoptosis and reduces proliferation in CML cell lines and LSCs, with minimal impact on normal hematopoietic stem cells (HSCs).
- FBXO3 interacts with DUSP9, promoting its ubiquitination and activating the MAPK pathway, which is critical for CML cell activity.
- DUSP9 knockdown partially reverses the effects of FBXO3 deficiency on LSC elimination.
- FBXO3 inhibitor monotherapy or combination with imatinib effectively eradicates CML-LSCs and overcomes TKI resistance while sparing normal hematopoiesis.
- The findings support combining FBXO3 inhibitors with TKIs for durable elimination of leukemia stem cells in CML.