Stromal-induced epithelial-mesenchymal transition induces targetable drug resistance in acute lymphoblastic leukemia
Chun Shik Park,
Hiroki Yoshihara,
Qingsong Gao,
Chunxu Qu,
Ilaria Iacobucci,
Pankaj S. Ghate,
Jon P. Connelly,
Shondra M. Pruett-Miller,
Ben Wagner,
Camenzind G. Robinson,
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
Affiliations
Chun Shik Park
Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
Hiroki Yoshihara
Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
Qingsong Gao
Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
Chunxu Qu
Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
Ilaria Iacobucci
Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
Pankaj S. Ghate
Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
Jon P. Connelly
Center for Advanced Genome Engineering, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA; Department of Cell and Molecular Biology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
Shondra M. Pruett-Miller
Center for Advanced Genome Engineering, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA; Department of Cell and Molecular Biology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
Ben Wagner
Cell and Tissue Imaging Center, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
Camenzind G. Robinson
Cell and Tissue Imaging Center, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
Ashutosh Mishra
Center for Proteomics and Metabolomics, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
Junmin Peng
Center for Proteomics and Metabolomics, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA; Department of Structural Biology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA; Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
Lei Yang
Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
Zoran Rankovic
Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
David Finkelstein
Department of Computational Biology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
Selina Luger
Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19106, USA
Mark Litzow
Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA
Elisabeth M. Paietta
Department of Oncology, Montefiore Medical Center, Bronx, NY 10460, USA
Nikhil Hebbar
Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
M. Paulina Velasquez
Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
Charles G. Mullighan
Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA; Corresponding author
Summary: The bone marrow microenvironment (BME) drives drug resistance in acute lymphoblastic leukemia (ALL) through leukemic cell interactions with bone marrow (BM) niches, but the underlying mechanisms remain unclear. Here, we show that the interaction between ALL and mesenchymal stem cells (MSCs) through integrin β1 induces an epithelial-mesenchymal transition (EMT)-like program in MSC-adherent ALL cells, resulting in drug resistance and enhanced survival. Moreover, single-cell RNA sequencing analysis of ALL-MSC co-culture identifies a hybrid cluster of MSC-adherent ALL cells expressing both B-ALL and MSC signature genes, orchestrated by a WNT/β-catenin-mediated EMT-like program. Blockade of interaction between β-catenin and CREB binding protein impairs the survival and drug resistance of MSC-adherent ALL cells in vitro and results in a reduction in leukemic burden in vivo. Targeting of this WNT/β-catenin-mediated EMT-like program is a potential therapeutic approach to overcome cell extrinsically acquired drug resistance in ALL.
