TY - JOUR
T1 - Tyrosine kinase inhibitors induce mesenchymal stem cell-mediated resistance in BCR-ABL+ acute lymphoblastic leukemia
AU - Mallampati, Saradhi
AU - Leng, Xiaohong
AU - Ma, Haiqing
AU - Zeng, Jianfang
AU - Li, June
AU - Wang, Haiying
AU - Lin, Kevin
AU - Lu, Yue
AU - Yang, Yang
AU - Sun, Baohua
AU - Gong, Yun
AU - Lee, Ju Seog
AU - Konopleva, Marina
AU - Andreeff, Michael
AU - Arlinghaus, Ralph B.
AU - Cai, Zhen
AU - Fang, Bingliang
AU - Shen, Haifa
AU - Han, Xin
AU - Hirsch-Ginsberg, Cheryl F.
AU - Gao, Xiaolian
AU - Paranjape, Anurag N.
AU - Mani, Sendurai A.
AU - Clise-Dwyer, Karen
AU - Sun, Xiaoping
N1 - Funding Information:
The authors thank K. Dorshkind (The University of California, Los Angeles, Jonsson Comprehensive Cancer Center) for help with pro-B-cell culturing; H. Pelicano and K. Harutyunyan for discussions; K. Ramirez, K. Acklin, D. Bonilla, R. Jewell, and D. Dwyer for help with flow cytometry sorting; and C. Robertson (University of Houston) for proofreading the manuscript. This study was supported by the National Institutes of Health, National Institute of Allergy and Infectious Diseases grant 1R21AI103652-01A1 (X.S.), an American Cancer Society Research Scholar grant (X.S.), The University of Texas MD Anderson Cancer Center Institutional Research grant (X.S.), a Leukemia SPORE Developmental Research Award (X.S.) and the MD Anderson Cancer Center Support grant from the National Institutes of Health, National Cancer Institute (CA016672).
Publisher Copyright:
© 2015 by The American Society of Hematology.
PY - 2015
Y1 - 2015
N2 - Tyrosine kinase inhibitors (TKIs) are used as a frontline therapy for BCR-ABL+ acute lymphoblastic leukemia (ALL). However, resistance to TKI therapy arises rapidly, and its underlying molecular mechanisms are poorly understood. In this study, we identified a novel cascade of events initiated by TKIs and traversing through mesenchymal stem cells (MSCs) to leukemic cells, leading to resistance. MSCs exposed to TKIs acquired a new functional status with the expression of genes encoding for chemo-attractants, adhesion molecules, and prosurvival growth factors, and this priming enabled leukemic cells to form clusters underneath the MSCs. This cluster formation was associated with the protection of ALL cells from therapy as leukemic cells switched from BCR-ABL signaling to IL-7R/Janus kinase signaling to survive in the MSC milieu. Our findings illustrate a novel perspective in the evolution of TKI resistance and provide insights for advancing the treatment of BCR-ABL+ ALL.
AB - Tyrosine kinase inhibitors (TKIs) are used as a frontline therapy for BCR-ABL+ acute lymphoblastic leukemia (ALL). However, resistance to TKI therapy arises rapidly, and its underlying molecular mechanisms are poorly understood. In this study, we identified a novel cascade of events initiated by TKIs and traversing through mesenchymal stem cells (MSCs) to leukemic cells, leading to resistance. MSCs exposed to TKIs acquired a new functional status with the expression of genes encoding for chemo-attractants, adhesion molecules, and prosurvival growth factors, and this priming enabled leukemic cells to form clusters underneath the MSCs. This cluster formation was associated with the protection of ALL cells from therapy as leukemic cells switched from BCR-ABL signaling to IL-7R/Janus kinase signaling to survive in the MSC milieu. Our findings illustrate a novel perspective in the evolution of TKI resistance and provide insights for advancing the treatment of BCR-ABL+ ALL.
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U2 - 10.1182/blood-2014-05-576421
DO - 10.1182/blood-2014-05-576421
M3 - Article
C2 - 25712988
AN - SCOPUS:84964698298
VL - 125
SP - 2968
EP - 2973
JO - Blood
JF - Blood
SN - 0006-4971
IS - 19
ER -