title: Adult T-cell leukemia cells overexpress Wnt5a and promote osteoclast differentiation.
abstract: Adult T-cell leukemia/lymphoma (ATL) is etiologically linked to infection with the human T-cell leukemia/lymphoma virus type 1 (HTLV-I). ATL is classified into 4 distinct clinical diseases: acute, lymphoma, chronic, and smoldering. Acute ATL is the most aggressive form, representing 60% of cases and has a 4-year survival of < 5%. A frequent complication and cause of death in acute ATL patients is the presence of lytic bone lesions and hypercalcemia. We analyzed the Wnt/β-catenin pathway because of its common role in cancer and bone remodeling. Our study demonstrated that ATL cells do not express high levels of β-catenin but displayed high levels of LEF-1/TCF genes along with elevated levels of β-catenin (LEF-1/TCF target genes) responsive genes. By profiling Wnt gene expression, we discovered that ATL patient leukemia cells shifted expression toward the noncanonical Wnt pathway. Interestingly, ATL cells overexpressed the osteolytic-associated genes-Wnt5a, PTHLH, and RANKL. We further show that Wnt5a secreted by ATL cells favors osteoclast differentiation and expression of RANK. Our results suggest that Wnt5a is a major contributing factor to the increase in osteolytic bone lesions and hypercalcemia found in ATL patients. Anti-Wnt5a therapy may prevent or reduce osteolytic lesions found in ATL patients and improve therapy outcome.
authors: Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Center for Viral Oncology, Kansas City, KS 66160, USA.
authors: Marcia
authors: M
authors: Bellon
authors: Nga Ling
authors: NL
authors: Ko
authors: Min-Jung
authors: MJ
authors: Lee
authors: Yuan
authors: Y
authors: Yao
authors: Thomas A
authors: TA
authors: Waldmann
authors: Jane B
authors: JB
authors: Trepel
authors: Christophe
authors: C
authors: Nicot
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000502:physiology; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D005434:Flow Cytometry; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D010010:Osteoclasts / Q000166:cytology*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis*; D060888:Real-Time Polymerase Chain Reaction; D059467:Transcriptome; D051153:Wnt Proteins / Q000096:biosynthesis*; D000071818:Wnt-5a Protein
chemical_list: D011518:Proto-Oncogene Proteins; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein
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