Tyrosine kinase inhibitors induce mesenchymal stem cell-mediated resistance in BCR-ABL+ acute lymphoblastic leukemia

Saradhi Mallampati, Xiaohong Leng, Haiqing Ma, Jianfang Zeng, June Li, Haiying Wang, Kevin Lin, Yue Lu, Yang Yang, Baohua Sun, Yun Gong, Ju Seog Lee, Marina Konopleva, Michael Andreeff, Ralph B. Arlinghaus, Zhen Cai, Bingliang Fang, Haifa Shen, Xin Han, Cheryl F. Hirsch-GinsbergXiaolian Gao, Anurag N. Paranjape, Sendurai A. Mani, Karen Clise-Dwyer, Xiaoping Sun

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2968-2973
Number of pages6
JournalBlood
Volume125
Issue number19
DOIs
StatePublished - 2015

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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