Stromal-induced epithelial-mesenchymal transition induces targetable drug resistance in acute lymphoblastic leukemia

• DOI: 10.1016/j.celrep.2023.112804
• Publication Date: 2023-07-14T23:10:52Z
• Authors: Chun Shik Park; Hiroki Yoshihara; Qingsong Gao; Chunxu Qu; Ilaria Iacobucci; Pankaj S. Ghate; Jon P. Connelly; Shondra M. Pruett...; Ben Wagner; Camenzind G. Robi...; Ashutosh Mishra; Junmin Peng; Lei Yang; Zoran Rankovic; David Finkelstein; Selina Luger; Mark Litzow; Elisabeth M. Paietta; Nikhil Hebbar; M. Paulina Velasquez; Charles G. Mullighan
• Keywords: Epithelial-Mesenchymal Transition; QH301-705.5; Drug Resistance; Tumor Microenvironment; Humans; Biology (General); Precursor Cell Lymphoblastic Leukemia-Lymphoma; CP: Cancer; Article; beta Catenin; Coculture Techniques; 3. Good health; Cell Proliferation

The bone marrow microenvironment (BME) drives drug resistance in acute lymphoblastic leukemia (ALL) through leukemic cell interactions with (BM) niches, but the underlying mechanisms remain unclear. Here, we show that interaction between ALL and mesenchymal stem cells (MSCs) integrin β1 induces an epithelial-mesenchymal transition (EMT)-like program MSC-adherent cells, resulting enhanced survival. Moreover, single-cell RNA sequencing analysis of ALL-MSC co-culture identifies a hybrid cluster expressing both B-ALL MSC signature genes, orchestrated by WNT/β-catenin-mediated EMT-like program. Blockade β-catenin CREB binding protein impairs survival vitro results reduction burden vivo. Targeting this is potential therapeutic approach to overcome extrinsically acquired ALL.