ATRA treatment of mice with AML driven by constitutive activation of b-catenin signaling in their osteoblasts

All-trans-retinoic acid (ATRA), an effective treatment for acute promyelocytic leukemia, but with disparate results in MDS and AML (de The,H. et al., Cell 1991; Geoffroy et al., Blood 2021), inhibits b-catenin activation in osteoblasts; a potent, niche-driven leukemogenic pathway seen in over a third of MDS and AML patients (Kode et al., Nature, 2014; Stoddart et al, Blood 2017; Bhagat et al., Cancer Res 2017). Inhibition of b-catenin signaling in osteoblasts by ATRA rescued mice with this pathway active (bcat(ex3)osb mice) from AML. We conducted whole exome sequencing analysis in T- and B- cell depleted (and CD3+ T-cell enriched) bone marrow cells from bcat(ex3)osb mice that responded or not to ATRA treatment and their wild littermates to test whether responsiveness to ATRA was associated with the presence of specific mutations in their hematopoietic cells.