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

Katsuyoshi Takata, Ken Saito, Satoshi Maruyama, Tomoko Miyata-Takata, Hidekazu Iioka, Shujiro Okuda, Yiwei Ling, Kennosuke Karube, Yukari Miki, Yoshinobu Maeda, Tadashi Yoshino, Christian Steidl, Eisaku Kondo

Research output: Contribution to journalArticle

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Abstract

Despite receiving rituximab-combined chemotherapy, follicular lymphoma (FL) patients often suffer tumor recurrence and understand that the cause of relapse in FL would thus significantly ameliorate the tumor therapeutics. In the present study, we show that TRA-1-60-expressing cells are a unique population in FL, 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 in scattered lymphoma cells in FL tissues only as well as in resting B-lymphocytes inside germinal centers. Retrospective comparison between recurrent and cognate primary tissues showed that the number of TRA-1-60-positive cells from rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone (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 10-fold compared to the untreated sample. Concordantly, scanty TRA-1-60-positive FL-18 cells implanted s.c. into mice evinced potent tumor-initiating capacity in vivo, where tumors were 12-fold larger in volume (P = 0.0021 < 0.005) and 13-fold heavier in weight (P = 0.0015 < 0.005) compared to those xenografted from TRA-negative cells. To explain these results, gene expression profiling and qPCR analysis indicated that TRA-1-60-positive cells defined a distinct population from that of 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 conventional therapeutic agents, which may explain its refractory recurrence.

Original languageEnglish
JournalCancer Science
DOIs
Publication statusAccepted/In press - Jan 1 2018

Fingerprint

Follicular Lymphoma
Population
Recurrence
Lymphoma
Neoplasms
Germinal Center
Gene Expression Profiling
Vincristine
Prednisone
Cyclophosphamide
B-Lymphocytes
Up-Regulation
Stem Cells
Therapeutics
Cell Count
Weights and Measures
Drug Therapy
Cell Line

Keywords

  • drug resistance
  • follicular lymphoma
  • rituximab
  • TRA-1-60
  • tumor recurrence

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Takata, K., Saito, K., Maruyama, S., Miyata-Takata, T., Iioka, H., Okuda, S., ... Kondo, E. (Accepted/In press). Identification of TRA-1-60-positive cells as a potent refractory population in follicular lymphomas. Cancer Science. https://doi.org/10.1111/cas.13870

Identification of TRA-1-60-positive cells as a potent refractory population in follicular lymphomas. / Takata, Katsuyoshi; Saito, Ken; Maruyama, Satoshi; Miyata-Takata, Tomoko; Iioka, Hidekazu; Okuda, Shujiro; Ling, Yiwei; Karube, Kennosuke; Miki, Yukari; Maeda, Yoshinobu; Yoshino, Tadashi; Steidl, Christian; Kondo, Eisaku.

In: Cancer Science, 01.01.2018.

Research output: Contribution to journalArticle

Takata, K, Saito, K, Maruyama, S, Miyata-Takata, T, Iioka, H, Okuda, S, Ling, Y, Karube, K, Miki, Y, Maeda, Y, Yoshino, T, Steidl, C & Kondo, E 2018, 'Identification of TRA-1-60-positive cells as a potent refractory population in follicular lymphomas', Cancer Science. https://doi.org/10.1111/cas.13870
Takata, Katsuyoshi ; Saito, Ken ; Maruyama, Satoshi ; Miyata-Takata, Tomoko ; Iioka, Hidekazu ; Okuda, Shujiro ; Ling, Yiwei ; Karube, Kennosuke ; Miki, Yukari ; Maeda, Yoshinobu ; Yoshino, Tadashi ; Steidl, Christian ; Kondo, Eisaku. / Identification of TRA-1-60-positive cells as a potent refractory population in follicular lymphomas. In: Cancer Science. 2018.
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abstract = "Despite receiving rituximab-combined chemotherapy, follicular lymphoma (FL) patients often suffer tumor recurrence and understand that the cause of relapse in FL would thus significantly ameliorate the tumor therapeutics. In the present study, we show that TRA-1-60-expressing cells are a unique population in FL, 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 in scattered lymphoma cells in FL tissues only as well as in resting B-lymphocytes inside germinal centers. Retrospective comparison between recurrent and cognate primary tissues showed that the number of TRA-1-60-positive cells from rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone (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 10-fold compared to the untreated sample. Concordantly, scanty TRA-1-60-positive FL-18 cells implanted s.c. into mice evinced potent tumor-initiating capacity in vivo, where tumors were 12-fold larger in volume (P = 0.0021 < 0.005) and 13-fold heavier in weight (P = 0.0015 < 0.005) compared to those xenografted from TRA-negative cells. To explain these results, gene expression profiling and qPCR analysis indicated that TRA-1-60-positive cells defined a distinct population from that of 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 conventional therapeutic agents, which may explain its refractory recurrence.",
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AU - Okuda, Shujiro

AU - Ling, Yiwei

AU - Karube, Kennosuke

AU - Miki, Yukari

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AU - Steidl, Christian

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AB - Despite receiving rituximab-combined chemotherapy, follicular lymphoma (FL) patients often suffer tumor recurrence and understand that the cause of relapse in FL would thus significantly ameliorate the tumor therapeutics. In the present study, we show that TRA-1-60-expressing cells are a unique population in FL, 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 in scattered lymphoma cells in FL tissues only as well as in resting B-lymphocytes inside germinal centers. Retrospective comparison between recurrent and cognate primary tissues showed that the number of TRA-1-60-positive cells from rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone (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 10-fold compared to the untreated sample. Concordantly, scanty TRA-1-60-positive FL-18 cells implanted s.c. into mice evinced potent tumor-initiating capacity in vivo, where tumors were 12-fold larger in volume (P = 0.0021 < 0.005) and 13-fold heavier in weight (P = 0.0015 < 0.005) compared to those xenografted from TRA-negative cells. To explain these results, gene expression profiling and qPCR analysis indicated that TRA-1-60-positive cells defined a distinct population from that of 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 conventional therapeutic agents, which may explain its refractory recurrence.

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