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  • 1
    Online Resource
    Online Resource
    Ovid Technologies (Wolters Kluwer Health) ; 2002
    In:  Current Opinion in Oncology Vol. 14, No. 2 ( 2002-03), p. 147-151
    In: Current Opinion in Oncology, Ovid Technologies (Wolters Kluwer Health), Vol. 14, No. 2 ( 2002-03), p. 147-151
    Type of Medium: Online Resource
    ISSN: 1040-8746
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2002
    detail.hit.zdb_id: 2026986-9
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  • 2
    Online Resource
    Online Resource
    American Society of Hematology ; 2004
    In:  Blood Vol. 104, No. 11 ( 2004-11-16), p. 2476-2476
    In: Blood, American Society of Hematology, Vol. 104, No. 11 ( 2004-11-16), p. 2476-2476
    Abstract: We recently demonstrated that multiple myeloma (MM) is organized in a hierarchical manner in which clonogenic MM progenitors or stem cells resembling post-germinal B cells give rise to MM plasma cells (PC). To study the potential biologic differences between MM stem cells and MM PC, we examined each cellular subset for characteristics found in normal stem cells as well as their responses to various antitumor agents. The human MM cell lines RPMI 8226 and NCI-H929 were initially studied as we previously found that they recapitulate clinical MM specimens and consist of distinct cell populations based on the expression of the PC surface antigen CD138; CD138+ cells resemble typical MM PC, whereas CD138neg cells express B cell surface antigens and have greater clonogenic capacity. Examination of these cellular subpopulations by flow cytometry demonstrated that CD138neg cells were smaller and less granular by light scatter than CD138+ PC and expressed higher levels of the intracellular enzyme aldehyde dehydrogenase that is present in normal hematopoietic progenitors with self-renewal potential. Furthermore, cells expressing the side population phenotype after staining with the DNA binding dye Hoechst 33342 were exclusively CD138neg. We also investigated the effects of different clinically applicable agents on CD138+ and CD138neg cells. CD138+ and CD138neg cells isolated from RPMI 8226 and NCI-H929 cells by fluorescence activated cell sorting were treated with dexamethasone (dex, 100nM), bortezomib (velcade, 10nM), CC5013 (revlimid, 1μM), rituximab (10μg/ml) or alemtuzumab (campath,10μg/ml) for 72 hours followed by plating in methylcellulose to assess clonogenic capacity. CD138+ PC were significantly inhibited by dex (27 ± 11% recovery compared to untreated control cells), velcade (14 ± 6%) and revlimid (44 ± 27%), whereas rituximab (92 ± 25%) and campath (97 ± 18%) had little activity. In contrast, clonogenic growth of CD138neg cells was not significantly inhibited by dex (82 ± 19%), velcade (88 ± 29%), or revlimid (91 ± 14%), but was significantly decreased by rituximab (63 ± 22%) and campath (47 ± 27%). Similarly, clonogenic MM growth of CD138neg cells from 4 clinical MM samples was not affected by dex (84 ± 9%), velcade (82 ± 24%), or revlimid (93 ± 11%), but was significantly inhibited by rituximab (19 ± 7%) or campath (15 ± 11%). Clonogenic MM precursors may be distinguished from MM PC by a variety of biological parameters typically expressed by normal stem cells. Furthermore, these cellular subsets have different susceptibilities to a variety of clinical agents, and agents with activity against MM PC may be ineffective against MM stem cells. Moreover, agents without activity agasint MM PC may have major activity against MM stem cells. The divergent sensitivities of MM stem cells and PC may explain the dramatic, but transient, responses seen with many agents. Therapeutic strategies that result in long-term remissions may require the inhibition of both MM PC to reduce clinical symptoms and MM stem cells responsible for relapse.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2004
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  • 3
    Online Resource
    Online Resource
    American Society of Hematology ; 2004
    In:  Blood Vol. 103, No. 6 ( 2004-03-15), p. 2332-2336
    In: Blood, American Society of Hematology, Vol. 103, No. 6 ( 2004-03-15), p. 2332-2336
    Abstract: 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 ( & lt; 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.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2004
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 4
    In: Biology of Blood and Marrow Transplantation, Elsevier BV, Vol. 9, No. 5 ( 2003-05), p. 312-319
    Type of Medium: Online Resource
    ISSN: 1083-8791
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2003
    detail.hit.zdb_id: 3056525-X
    detail.hit.zdb_id: 2057605-5
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  • 5
    In: Journal of Interferon & Cytokine Research, Mary Ann Liebert Inc, Vol. 24, No. 1 ( 2004-01), p. 37-41
    Type of Medium: Online Resource
    ISSN: 1079-9907 , 1557-7465
    Language: English
    Publisher: Mary Ann Liebert Inc
    Publication Date: 2004
    detail.hit.zdb_id: 1483128-4
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  • 6
    In: British Journal of Haematology, Wiley, Vol. 121, No. 2 ( 2003-04), p. 251-258
    Abstract: Summary. Interferon‐alpha (IFN‐α) is a pleotropic cytokine that has clinical activity against a wide variety of malignancies, including multiple myeloma (MM). In vitro , IFN‐α has diverse effects on both normal and malignant cells, however, the exact mechanisms responsible for its clinical anti‐tumour activity remain unclear. We found that IFN‐α inhibited MM cell proliferation in association with cell cycle arrest at G 1 and limited the clonogenic growth of both MM cell lines and primary patient specimens. At the doses tested, IFN‐α was not cytotoxic, but induced terminal plasma cell differentiation resulting in the loss of clonogenicity. These activities were markedly enhanced by the major MM growth factor interleukin 6 (IL‐6). Moreover, IL‐6 was required for this process, as neutralizing antibodies against IL‐6 inhibited the effects of IFN‐α. IL‐6 also induced MM cell terminal differentiation when combined with a second, unrelated, antiproliferative agent bryostatin‐1, suggesting that its differentiating activities are preferentially enhanced in the presence of agents that inhibit cell cycling. These results suggest that the differentiating activities of IFN‐α may play a role in its clinical antimyeloma activity and provide the rationale for clinical differentiation therapy in MM.
    Type of Medium: Online Resource
    ISSN: 0007-1048 , 1365-2141
    RVK:
    Language: English
    Publisher: Wiley
    Publication Date: 2003
    detail.hit.zdb_id: 1475751-5
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  • 7
    In: Blood, American Society of Hematology, Vol. 104, No. 11 ( 2004-11-16), p. 1996-1996
    Abstract: Imatinib has largely replaced interferon-alpha (IFN) as front-line therapy in the treatment of chronic myeloid leukemia (CML) because of its favorable toxicity profile and superior initial response rate. However, recent laboratory data demonstrating that CML stem cells may have limited susceptibility to imatinib brings into question the potential durability of these responses. In contrast, responses to IFN often take place over months or years, but extensive long-term clinical data indicate that they are often long lasting. In order to determine if the differences in clinical response kinetics could be explained by the activity of imatinib and IFN against CML stem cells or their differentiated progeny, we examined the effects of each agent on distinct cellular subsets in vitro. CD34+ CML progenitors were isolated from 4 patients with newly diagnosed chronic phase CML and incubated with IFN (1000U/ml) or imatinib (10μM) for 96 hours followed by long-term liquid culture over 1-3 weeks to assay more primitive CML stem cells. The effects of each drug on CML progenitors was determined by calculating the number of CFU-GM positive for BCR-ABL by FISH and comparing these values to the bcr-abl+ CFU-GM formed by untreated control cells. Initially, the CML CFU-GM recovery immediately following 96 hours of drug treatment was 62.7 ± 8% and 9.7 ± 2% from IFN and imatinib-treated groups, respectively. After 3 weeks of long-term culture, CML CFU-GM recovery was 23.4 ± 2.6% following IFN treatment and 57.3 ± 22% after imatinib. Thus, imatinib was significantly more toxic to committed CML progenitors than primitive CML progenitors responsible for the maintenance of long-term liquid cultures (p = 0.04). Conversely, IFN had significantly greater activity against primitive CML progenitors than committed progenitors (p = 0.05). Although IFN has diverse biological properties, the mechanisms responsible for its antileukemic activity are unknown. Treatment of the human CML cell line KT-1 with IFN resulted in increased expression of the myeloid antigens CD33 and myeloperoxidase as well as the inhibition of clonogenic growth demonstrating that IFN induced terminal differentiation. Furthermore, several groups have shown that myeloid growth factors also induce differentiation of CML cells in vitro and clinically enhance the activity of IFN; accordingly, the addition of GM-CSF (200U/ml) augmented the differentiation of KT-1 cells. Moreover, myeloid growth factors were required for differentiation as neutralizing antibodies against GM-CSF and IL-3 inhibited the activity of IFN. The addition of GM-CSF to IFN produced similar effects on clinically derived CD34+ CML cells. Although imatinib is a potent inhibitor of committed CML progenitors, it is relatively ineffective against more primitive CML stem cells. In contrast, IFN appears to act primarily against CML stem cells by inducing terminal differentiation that is dependent on the activity of myeloid growth factors. Imatinib and IFN have divergent effects on CML progenitors at different stages of maturation that may correlate with clinical response kinetics and durability.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2004
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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