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

doi:10.1016/j.celrep.2023.112804

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 VelasquezCharles G. Mullighan

Oncology

Research output: Contribution to journal › Article › peer-review

7 Scopus citations

Abstract

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.

Original language	English (US)
Article number	112804
Journal	Cell Reports
Volume	42
Issue number	7
DOIs	https://doi.org/10.1016/j.celrep.2023.112804
State	Published - Jul 25 2023

Keywords

ALL
CP: Cancer
WNT
acute lymphoblastic leukemia
bone marrow microenvironment
cell adhesion
cell-cell interaction
chemoresistance
drug resistance
epithelial-mesenchymal transition
mesenchymal stem cell

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.celrep.2023.112804

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Park, C. S., Yoshihara, H., Gao, Q., Qu, C., Iacobucci, I., Ghate, P. S., Connelly, J. P., Pruett-Miller, S. M., Wagner, B., Robinson, C. G., Mishra, A., Peng, J., Yang, L., Rankovic, Z., Finkelstein, D., Luger, S., Litzow, M., Paietta, E. M., Hebbar, N., ... Mullighan, C. G. (2023). Stromal-induced epithelial-mesenchymal transition induces targetable drug resistance in acute lymphoblastic leukemia. Cell Reports, 42(7), Article 112804. https://doi.org/10.1016/j.celrep.2023.112804

Park, CS, Yoshihara, H, Gao, Q, Qu, C, Iacobucci, I, Ghate, PS, Connelly, JP, Pruett-Miller, SM, Wagner, B, Robinson, CG, Mishra, A, Peng, J, Yang, L, Rankovic, Z, Finkelstein, D, Luger, S, Litzow, M, Paietta, EM, Hebbar, N, Velasquez, MP & Mullighan, CG 2023, 'Stromal-induced epithelial-mesenchymal transition induces targetable drug resistance in acute lymphoblastic leukemia', Cell Reports, vol. 42, no. 7, 112804. https://doi.org/10.1016/j.celrep.2023.112804

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title = "Stromal-induced epithelial-mesenchymal transition induces targetable drug resistance in acute lymphoblastic leukemia",

abstract = "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.",

keywords = "ALL, CP: Cancer, WNT, acute lymphoblastic leukemia, bone marrow microenvironment, cell adhesion, cell-cell interaction, chemoresistance, drug resistance, epithelial-mesenchymal transition, mesenchymal stem cell",

author = "Park, {Chun Shik} and Hiroki Yoshihara and Qingsong Gao and Chunxu Qu and Ilaria Iacobucci and Ghate, {Pankaj S.} and Connelly, {Jon P.} and Pruett-Miller, {Shondra M.} and Ben Wagner and Robinson, {Camenzind G.} and Ashutosh Mishra and Junmin Peng and Lei Yang and Zoran Rankovic and David Finkelstein and Selina Luger and Mark Litzow and Paietta, {Elisabeth M.} and Nikhil Hebbar and Velasquez, {M. Paulina} and Mullighan, {Charles G.}",

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year = "2023",

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doi = "10.1016/j.celrep.2023.112804",

language = "English (US)",

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AU - Park, Chun Shik

AU - Yoshihara, Hiroki

AU - Gao, Qingsong

AU - Qu, Chunxu

AU - Iacobucci, Ilaria

AU - Ghate, Pankaj S.

AU - Connelly, Jon P.

AU - Pruett-Miller, Shondra M.

AU - Wagner, Ben

AU - Robinson, Camenzind G.

AU - Mishra, Ashutosh

AU - Peng, Junmin

AU - Yang, Lei

AU - Rankovic, Zoran

AU - Finkelstein, David

AU - Luger, Selina

AU - Litzow, Mark

AU - Paietta, Elisabeth M.

AU - Hebbar, Nikhil

AU - Velasquez, M. Paulina

AU - Mullighan, Charles G.

PY - 2023/7/25

Y1 - 2023/7/25

N2 - 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.

AB - 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.

KW - ALL

KW - CP: Cancer

KW - WNT

KW - acute lymphoblastic leukemia

KW - bone marrow microenvironment

KW - cell adhesion

KW - cell-cell interaction

KW - chemoresistance

KW - drug resistance

KW - epithelial-mesenchymal transition

KW - mesenchymal stem cell

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ER -

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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