title: Galectin-3 (Gal-3) induced by leukemia microenvironment promotes drug resistance and bone marrow lodgment in chronic myelogenous leukemia.
abstract: Bone marrow (BM) microenvironment (BMME) constitutes the sanctuary for leukemic cells. In this study, we investigated the molecular mechanisms for BMME-mediated drug resistance and BM lodgment in chronic myelogenous leukemia (CML). Gene-expression profile as well as signal pathway and protein analyses revealed that galectin-3 (Gal-3), a member of the β-gal-binding galectin family of proteins, was specifically induced by coculture with HS-5 cells, a BM stroma cell-derived cell line, in all five CML cell lines examined. It was also found that primary CML cells expressed high levels of Gal-3 in BM. Enforced expression of Gal-3 activated Akt and Erk, induced accumulation of Mcl-1, and promoted in vitro cell proliferation, multidrug resistance to tyrosine kinase inhibitors for Bcr-Abl and genotoxic agents as a result of impaired apoptosis induction, and chemotactic cell migration to HS-5-derived soluble factors in CML cell lines independently of Bcr-Abl tyrosine kinase. The conditioned medium from Gal-3-overexpressing CML cells promoted in vitro cell proliferation of CML cells and HS-5 cells more than did the conditioned medium from parental cells. Moreover, the in vivo study in a mice transplantation model showed that Gal-3 overexpression promoted the long-term BM lodgment of CML cells. These results demonstrate that leukemia microenvironment-specific Gal-3 expression supports molecular signaling pathways for disease maintenance in BM and resistance to therapy in CML. They also suggest that Gal-3 may be a candidate therapeutic target to help overcome BMME-mediated therapeutic resistance.
authors: Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
authors: Mio
authors: M
authors: Yamamoto-Sugitani
authors: Junya
authors: J
authors: Kuroda
authors: Eishi
authors: E
authors: Ashihara
authors: Hisao
authors: H
authors: Nagoshi
authors: Tsutomu
authors: T
authors: Kobayashi
authors: Yosuke
authors: Y
authors: Matsumoto
authors: Nana
authors: N
authors: Sasaki
authors: Yuji
authors: Y
authors: Shimura
authors: Miki
authors: M
authors: Kiyota
authors: Ryuko
authors: R
authors: Nakayama
authors: Kenichi
authors: K
authors: Akaji
authors: Tomohiko
authors: T
authors: Taki
authors: Nobuhiko
authors: N
authors: Uoshima
authors: Yutaka
authors: Y
authors: Kobayashi
authors: Shigeo
authors: S
authors: Horiike
authors: Taira
authors: T
authors: Maekawa
authors: Masafumi
authors: M
authors: Taniwaki
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D017077:Culture Media, Conditioned; D019008:Drug Resistance, Neoplasm / Q000235:genetics / Q000502:physiology; D037502:Galectin 3 / Q000378:metabolism*; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008954:Models, Biological; D009368:Neoplasm Transplantation; D015398:Signal Transduction; D014183:Transplantation, Heterologous; D059016:Tumor Microenvironment / Q000235:genetics / Q000502:physiology
chemical_list: D017077:Culture Media, Conditioned; D037502:Galectin 3