Targeting BMP and TAZ/TEAD mechanotransduction pathways impairs acute myeloid leukemia chemoresistance

Despite extensive research and intensive use of chemotherapies in clinics, the 5-year overall survival of acute myeloid leukemia (AML) patients does not exceed 20%. The clonal expansion of leukemic blasts leads to modifications of the bone marrow physical properties, including increased extracellular matrix stiffening, upregulation of intramedullary pressure and reduction of the space available for cells. These biomechanical modifications are speculated to alter therapeutic response and cause treatment resistance. To address this, we herein focused on the role of mechanotransduction pathways in AML. Analysis of primary AML samples or cell lines revealed that BMPR1B and TAZ/TEAD but not YAP levels were higher after patient relapse or in cells resistant to cytarabine or venetoclax. In addition, highly confined resident mesenchymal stem cells expressed higher levels of BMP4, which in turn specifically activated AML-resistant cells. In these cells, TAZ expression was associated with improved adhesion to microenvironmental components and increased intrinsic deformability. Finally, using a 3D human bone marrow-like model, we showed that targeting BMPR1B or TAZ/TEAD in combination with cytarabine impaired persistence of AML primary cells within the AML niche. Future therapeutic approaches could involve BMPR1B and/or TAZ/TEAD targeting in the context of AML patients refractory to chemotherapy or after relapse.