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.

Intracellular galectins in cancer cells: Potential new targets for therapy

“…Galectin-3 has also been shown to modulate apoptosis. In myeloid leukemia, neuroblastoma, colorectal, breast, prostate, thyroid, bladder, pancreatic, gastric and some B-cell lymphoma cancer cells it has been shown to have anti-apoptotic functions (47,(65)(66)(67)(68)(69)(70)(71)(72)(73)(74)(75)(76)(77)(78)(79)(80). In contrast, it seems to induce apoptosis in other B-cell lymphomas (81).…”

Leucémie myéloïde chronique

“…Des études en cocultures ont montré la production de Gal-3 par plusieurs lignées humaines BCR-ABL + sous l'influence de cellules stromales HS-5 [24]. De plus, des taux élevés de Gal-3 ont été détec-tés dans les cellules leucémiques isolées de la moelle osseuse de patients atteints de LMC.…”

“…Dans le cas de la LMC, l'inhibition du PlGF pourrait avoir un effet additif à celui de l'imatinib [23]. Enfin, plusieurs autres cibles peuvent être envisagées comme la galectine-3 (utilisation du complexe polysaccharidique GCS-100 bloquant les effets de Gal-3) et l'ostéopontine (utilisation d'anticorps anti-OPN) [24,34]. souches de LMC.…”

Propagation of trimethylated H3K27 regulated by polycomb protein EED is required for embryogenesis, hematopoietic maintenance, and tumor suppression

“…These results indicate that derepression of Lgals3, a PRC2 target gene, contributes to the stemness of HSPCs. Human chronic myeloid leukemia cells overexpressing LGALS3 showed increased proliferation and cell accumulation in the BM in a xenograft model (21). Clinically, higher expression of LGALS3 is considered a poor prognostic factor for overall survival in patients with acute myeloid leukemia (22).…”