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Cancer Sci. 2018 Nov 11. doi: 10.1111/cas.13870. [Epub ahead of print]

Identification of TRA-1-60-positive cells as a potent refractory population in follicular lymphomas.

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Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8558, Japan.
Department of Hematology and Oncology, Okayama University Hospital, Okayama, 700-8558, Japan.
Division of Molecular and Cellular Pathology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, 951-8510, Japan.
Oral Pathology Section, Department of Surgical Pathology, Niigata University Hospital, Niigata, 951-8510, Japan.
Bioinformatics Laboratory, Niigata University Graduate School of Medical and Dental Sciences, Niigata, 951-8510, Japan.
Departments of Pathology and Cell Biology, Graduate School of Medicine, University of the Ryukyus, Nishihara, 903-0215, Japan.
Department of Medical Hygiene, Medical Technology Course, Kochi Gakuen Junior College, Kochi, 780-0955, Japan.
Centre for Lymphoid Cancer, BC Cancer Agency, Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.


Despite receiving rituximab-combined chemotherapy, follicular lymphoma (FL) patients often suffer tumor recurrence, and understand the cause of relapse in FL would thus significantly ameliorate the tumor therapeutics. Here we demonstrate that the TRA-1-60-expressing cells are a unique population in FLs, converge to the conventional stem cell marker Oct3/4 and ALDH1-positive population, and resist current B-lymphoma agents. TRA-1-60 expression was observed only in scattered lymphoma cells in FL tissues as well as resting B-lymphocytes inside germinal centers. Retrospective comparison between the recurrent and cognate primary tissues revealed that the number of TRA-1-60-positive cells from R-CHOP-treated FL had increased relative to primary tissue, a finding corroborated by assays on different rituximab-treated FL cell lines, FL-18 and DOHH2, wherein TRA-positive cell numbers increased over ten-fold compared to the untreated sample. Concordantly, scanty TRA-1-60-positive FL-18 cells implanted subcutaneously into mice evinced potent tumor-initiating capacity in vivo, where tumors were twelve-fold larger in volume (p=0.0021<0.005) and thirteen-fold heavier in weight (p=0.0015<0.005) compared to those xenografted from the TRA-negative cells. To explain these, gene expression profiling and the qPCR analysis indicated that the TRA-1-60-positive cells defined distinct population from that of the TRA-negative cells, with upregulation of multiple drug transporters and therapeutic resistance genes. Hence, TRA-1-60-expressing cells in FL are considered to be vigorously intractable against the conventional therapeutic agents, which may explain its refractory recurrence. This article is protected by copyright. All rights reserved.


Follicular lymphoma; TRA-1-60; drug resistance; rituximab; tumor recurrence

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