In:
Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 4122-4122
Abstract:
Despite receiving Rituximab-combined chemotherapy, approximately half of follicular lymphoma (FL) patients suffer tumor recurrence, a major clinical issue. Retrieval of lymphoma stem-like cells from these poorly understood, intractable lymphomas would thus greatly ameliorate the cancer 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 strongly resist current agents against B-cell lymphomas. TRA-1-60 expression was detected in minor populations of resting B-lymphocytes inside germinal centers in reactive lymphoid tissue, whereas scattered TRA-1-60-expressing cells were detected in the marginal area of neoplastic follicles of FLs, close to small blood vessels. Translocation t(14;18) was thus detected in DNAs from the TRA-positive cells in all five patients' samples, which evinced the identical pattern of gene fusion as that of TRA-negative cells in the same tissue in 4 of 5 fresh frozen FL samples. Retrospective histological comparison between the recurrent and cognate primary tissues revealed that the number of TRA-1-60-positive lymphoma cells from R-CHOP treated FL subjects had increased four-fold relative to primary tissue, a finding corroborated by in vitro assay on Rituximab treated 2 cell lines, wherein TRA-positive cell numbers increased over ten to thirty-fold compared to the untreated sample. Moreover, TRA-1-60-positive cell population was markedly resistant to current therapeutic agents for B-cell lymphomas. Concordantly, small numbers of TRA-1-60-positive cells implanted subcutaneously into NOD/SCID 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. In conclusion, while further investigation for molecular insights will be necessary, it is now clear that TRA-1-60 should be a prominent focus among cellular markers in follicular lymphoma research, by which we ultimately hope to explain clinical intractability against combination-Rituximab and other therapies, and to better understand the stemness among a range of lymphoma cell types. Disclosures Maeda: Mundipharma KK: Research Funding.
Type of Medium:
Online Resource
ISSN:
0006-4971
,
1528-0020
DOI:
10.1182/blood.V128.22.4122.4122
Language:
English
Publisher:
American Society of Hematology
Publication Date:
2016
detail.hit.zdb_id:
1468538-3
detail.hit.zdb_id:
80069-7
