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      Identification and characterization of the cellular subclones that contribute to the pathogenesis of mantle cell lymphoma


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          Mantle cell lymphoma (MCL) is a B-cell malignancy with poor clinical outcome and undefined pathogenesis. Development of clinically relevant cellular models for MCL research is an urgent need. Our preliminary observations lead the development of two novel hypotheses that we tested in this study: 1. multicellular spheroid might be a unique growth mode of early-stage cells in MCL; 2. MCL might be a polyclonal tumor. We made the following original observations that have not been reported: First, we have provided a new experiment method for enriching MCL early-stage cells and characterized the spheroid mode of growth as a unique feature of early-stage MCL cells in cell line as well as in clinical samples. Second, we have established a clinically relevant cellular model of MCL, the JeKo-1-spheroid cell line, that was highly enriched in early-stage sub-clones. JeKo-1-spheroid cells and the spheroid growing cells enriched from MCL patients exhibited comparably enhanced tumorigenic abilities and similar biological features. Third, Immunophenotypic analysis has revealed that MCL may be derived from precursor-B(pre-B), immature-B and mature-B cells, not only the mature-B cells as WHO classified in 2016. Fourth, MCL may be a polyclonal disease composed of CD19 /IgM , CD19 /IgM +, CD19 +/IgM + three sub-clones, of which the CD19 /IgM + sub-clone might be the dominant sub-clone with the strongest tumorigenic ability. Fifth, CD19 +/IgM that differentiates MCL and normal B cells may represent a new marker for MCL early detection, minor residual disease monitoring after therapies and prognosis.

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          Tracing the origins of relapse in acute myeloid leukaemia to stem cells

          In acute myeloid leukaemia, long-term survival is poor as most patients relapse despite achieving remission. Historically, the failure of therapy has been thought to be due to mutations that produce drug resistance, possibly arising as a consequence of the mutagenic properties of chemotherapy drugs. However, other lines of evidence have pointed to the pre-existence of drug-resistant cells. For example, deep sequencing of paired diagnosis and relapse acute myeloid leukaemia samples has provided direct evidence that relapse in some cases is generated from minor genetic subclones present at diagnosis that survive chemotherapy, suggesting that resistant cells are generated by evolutionary processes before treatment and are selected by therapy. Nevertheless, the mechanisms of therapy failure and capacity for leukaemic regeneration remain obscure, as sequence analysis alone does not provide insight into the cell types that are fated to drive relapse. Although leukaemia stem cells have been linked to relapse owing to their dormancy and self-renewal properties, and leukaemia stem cell gene expression signatures are highly predictive of therapy failure, experimental studies have been primarily correlative and a role for leukaemia stem cells in acute myeloid leukaemia relapse has not been directly proved. Here, through combined genetic and functional analysis of purified subpopulations and xenografts from paired diagnosis/relapse samples, we identify therapy-resistant cells already present at diagnosis and two major patterns of relapse. In some cases, relapse originated from rare leukaemia stem cells with a haematopoietic stem/progenitor cell phenotype, while in other instances relapse developed from larger subclones of immunophenotypically committed leukaemia cells that retained strong stemness transcriptional signatures. The identification of distinct patterns of relapse should lead to improved methods for disease management and monitoring in acute myeloid leukaemia. Moreover, the shared functional and transcriptional stemness properties that underlie both cellular origins of relapse emphasize the importance of developing new therapeutic approaches that target stemness to prevent relapse.
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            Characterization of clonogenic multiple myeloma cells.

            The identity of the cells responsible for the initiation and maintenance of multiple myeloma (MM) remains unclear largely because of the difficulty growing MM cells in vitro and in vivo. MM cell lines and clinical specimens are characterized by malignant plasma cells that express the cell surface antigen syndecan-1 (CD138); however, CD138 expression is limited to terminally differentiated plasma cells during B-cell development. Moreover, circulating B cells that are clonally related to MM plasma cells have been reported in some patients with MM. We found that human MM cell lines contained small (< 5%) subpopulations that lacked CD138 expression and had greater clonogenic potential in vitro than corresponding CD138+ plasma cells. CD138- cells from clinical MM samples were similarly clonogenic both in vitro and in nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice, whereas CD138+ cells were not. Furthermore, CD138- cells from both cell lines and clinical samples phenotypically resembled postgerminal center B cells, and their clonogenic growth was inhibited by the anti-CD20 monoclonal antibody rituximab. These data suggest that MM "stem cells" are CD138- B cells with the ability to replicate and subsequently differentiate into malignant CD138+ plasma cells.
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              Mantle cell lymphoma: biology, pathogenesis, and the molecular basis of treatment in the genomic era.

              Mantle cell lymphoma (MCL) is a B-cell non-Hodgkin lymphoma of which at least a subset arises from antigen-experienced B cells. However, what role antigen stimulation plays in its pathogenesis remains ill defined. The genetic hallmark is the chromosomal translocation t(11;14) resulting in aberrant expression of cyclin D1. Secondary genetic events increase the oncogenic potential of cyclin D1 and frequently inactivate DNA damage response pathways. In combination these changes drive cell-cycle progression and give rise to pronounced genetic instability. Several signaling pathways contribute to MCL pathogenesis, including the often constitutively activated PI3K/AKT/mTOR pathway, which promotes tumor proliferation and survival. WNT, Hedgehog, and NF-κB pathways also appear to be important. Although MCL typically responds to frontline chemotherapy, it remains incurable with standard approaches. Proteasome inhibitors (bortezomib), mTOR inhibitors (temsirolimus), and immunomodulatory drugs (lenalidomide) have recently been added to the treatment options in MCL. The molecular basis for the antitumor activity of these agents is an area of intense study that hopefully will lead to further improvements in the near future. Given its unique biology, relative rarity, and the difficulty in achieving long-lasting remissions with conventional approaches, patients with MCL should be encouraged to participate in clinical trials.

                Author and article information

                Genes Dis
                Genes Dis
                Genes & Diseases
                Chongqing Medical University
                21 December 2018
                December 2019
                21 December 2018
                : 6
                : 4
                : 407-418
                [a ]Laboratory of Translational Cancer Stem Cell Research, Institute of Life Sciences, Chongqing Medical University, 1 Yixueyuan Rd, Chongqing, 400016, China
                [b ]Department of Hematology, The Affiliated Hospital of Southwest Medical University, 25 Tai Ping Street, Luzhou, 646000, China
                [c ]The Affiliated Stomatology Hospital of Southwest Medical University, 2 Jiangyangnan Rd, Luzhou, 646000, China
                [d ]Department of Pathology, The Affiliated Hospital of Southwest Medical University, 25 Tai Ping Street, Luzhou, 646000, China
                [e ]Department of Hematology, Mianyang Central Hospital, 12 Changjia Lane, Jingzhong Street, Mianyang, 621000, China
                [f ]School of Biomedical Engineering, Chongqing Medical University, 1 Yixueyuan Rd, Chongqing, 400016, China
                Author notes
                []Corresponding author. Laboratory of Translational Cancer Stem Cell Research, Institute of Life Sciences, Chongqing Medical University, 1 Yixueyuan Rd, Chongqing, 400016, China. Xinglab310@ 123456163.com.CELL
                [∗∗ ]Corresponding author. zlroy2003@ 123456163.com
                [∗∗∗ ]Corresponding author. Wjy2003123@ 123456163.com

                These authors contributed equally.

                © 2018 Chongqing Medical University. Production and hosting by Elsevier B.V.

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                : 5 November 2018
                : 17 December 2018

                jeko-1-spheroid,mantle cell lymphoma,pathology,sub-clone,cd19


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