scholarly journals The CXCL12gamma chemokine immobilized by heparan sulfate on stromal niche cells controls adhesion and mediates drug resistance in multiple myeloma

2020 ◽  
Author(s):  
Zemin Ren ◽  
Hildo Lantermans ◽  
Annemieke Kuil ◽  
Willem Kraan ◽  
Fernando Arenzana-Seisdedos ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Drug Resistance ◽  
Cell Adhesion ◽  
Heparan Sulfate ◽  
Stromal Cells ◽  
Unique Role ◽  
Bm Niche ◽  
Strong Adhesion ◽  
Membrane Bound ◽  
Cell Adhesion Molecule 1

AbstractThe homing/retention, survival and proliferation of multiple myeloma (MM) cells critically depends on interaction with CXCL12 expressing stromal cells in the bone marrow (BM) niche. Here, we report a unique role in this interaction for the recently characterized CXCL12gamma isoform, which contains an extended C-terminal domain that binds heparan-sulfate proteoglycans (HSPGs) with an extraordinary high affinity. We observed that CXCL12γ is expressed in situ by reticular stromal cells in both normal and MM BM, as well as by primary BM stromal-cell (BMSC) isolates and BMSC lines. Importantly, upon secretion, CXCL12γ, unlike the CXCL12α isoform, was retained on the surface of these BMSCs. This membrane retention of CXCL12γ is HSPG-mediated, since it was completely annulated by CRISPR-Cas9 mediated deletion of the heparan-sulfate (HS) co-polymerase EXT1. Recombinant CXCL12γ was found to induce strong adhesion of MM cells to vascular cell-adhesion molecule 1 (VCAM-1) coated plates. Furthermore, CXCL12γ expressed by BMSCs and membrane-retained by HSPGs, supported robust adhesion of MM cells to the BMSCs. Specific genetic deletion of either CXCL12γ or of EXT1 significantly attenuated the ability of BMSCs to support MM cell adhesion and, in addition, impaired their capacity to protect MM cells from bortezomib-induced cell death. Our data indicate that CXCL12γ functions as a membrane-bound ‘niche chemokine’, which plays a unique role in the interaction of MM cells with the stromal niche by controlling adhesion/retention as well as cell adhesion-mediated drug resistance (CAM-DR). These findings designate CXCL12γ and associated HSPGs as potential therapeutic targets in MM.

scholarly journals The CXCL12gamma chemokine immobilized by heparan sulfate on stromal niche cells controls adhesion and mediates drug resistance in multiple myeloma

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Zemin Ren ◽  
Hildo Lantermans ◽  
Annemieke Kuil ◽  
Willem Kraan ◽  
Fernando Arenzana-Seisdedos ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Drug Resistance ◽  
Heparan Sulfate ◽  
Stromal Cells ◽  
Functional Roles ◽  
Bm Niche ◽  
Human Bmscs ◽  
Chemokine Cxcl12 ◽  
Mrna And Protein Expression ◽  
Membrane Bound

Abstract Background The survival and proliferation of multiple myeloma (MM) cells in the bone marrow (BM) critically depend on interaction with stromal cells expressing the chemokine CXCL12. CXCL12 regulates the homing to the BM niche by mediating the transendothelial migration and adhesion/retention of the MM cells. The gamma isoform of CXCL12 (CXCL12γ) has been reported to be highly expressed in mouse BM and to show enhanced biological activity compared to the ‘common’ CXCL12α isoform, mediated by its unique extended C-terminal domain, which binds heparan sulfate proteoglycans (HSPGs) with an extraordinary high affinity. Here, we investigated the expression of CXCL12γ in human BM and studied its functional role in the interaction of MM cells with BM stromal cells (BMSCs). Methods We assessed CXCL12γ mRNA and protein expression by human BMSCs using qPCR, flow cytometry, and immunohistochemistry. CRISPR-Cas9 was employed to delete CXCL12γ and the heparan sulfate (HS) co-polymerase EXT1 in BMSCs. To study the functional roles of BMSC-derived CXCL12γ and HSPGs in the interaction of MM cells with BMSCs cells, MM cell lines and primary MM cells were co-cultured with BMSCs. Results We observed that CXCL12γ is expressed in situ by reticular stromal cells in both normal and MM BM, as well as by primary BMSC isolates and BMSC lines. Importantly, upon secretion, CXCL12γ, unlike the CXCL12α isoform, was retained on the surface of BMSCs. This membrane retention of CXCL12γ is HSPG mediated, since it was completely annulated by CRISPR-Cas9-mediated deletion of the HS co-polymerase EXT1. CXCL12γ expressed by BMSCs and membrane-retained by HSPGs supported robust adhesion of MM cells to the BMSCs. Specific genetic deletion of either CXCL12γ or EXT1 significantly attenuated the ability of BMSCs to support MM cell adhesion and, in addition, impaired their capacity to protect MM cells from bortezomib-induced cell death. Conclusions We show that CXCL12γ is expressed by human BMSCs and upon secretion is retained on their cell surface by HSPGs. The membrane-bound CXCL12γ controls adhesion of MM cells to the stromal niche and mediates drug resistance. These findings designate CXCL12γ and associated HSPGs as partners in mediating MM–niche interaction and as potential therapeutic targets in MM.

The Wiskott Aldrich Syndrome Protein (WASP) Is Involved in Dexamethasone-Signalling Pathways Leading to Apoptosis of Multiple Myeloma Cells and in Cell Adhesion Mediated Drug Resistance Against Dexamethasone

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1809-1809
Author(s):  
Hazera Khatun ◽  
Amna Anwar ◽  
Majid A. Kazmi ◽  
Stephen Schey ◽  
Yolanda Calle
Keyword(s):  
Multiple Myeloma ◽  
Drug Resistance ◽  
Cell Death ◽  
Cell Adhesion ◽  
Cell Line ◽  
Stromal Cells ◽  
Signalling Pathway ◽  
Actin Dynamics ◽  
Signalling Pathways ◽  
Syndrome Protein

Abstract Abstract 1809 Direct contact of multiple myeloma (MM) cells with the bone marrow (BM) stroma promotes cell survival leading to cell adhesion mediated drug resistance (CAM-DR). Dexamethasone is a conventional anti-MM drug that effectively induces MM cell death at presentation and in relapsed patients but the signalling pathways involved in its mechanisms of action are not completely understood. Resistance of MM to Dexamethasone may result from genetic changes in MM cells or through the contact of MM cells with the BM microenvironment. It has been shown that CAM-DR blocks the effect of Dexamethasone by the binding of MM cells to the BM stroma. Our data indicate a key role of the binding of MM CXCR4 receptor on stromal cell derived SDF1-a in CAM-DR against Dexamethasone. Dexamethasone induced upregulation of CXCR4 in the MM1.S cell line (sensitive to Dexamethasone) whilst, as expected, having no effect on the MM1.R cell line (resistant to Dexamethasone by expression of a mutated form of the glucocorticoid receptor). Bortezomib induced down regulation of CXCR4 in both MM1.S and MM1.R cell lines in a dose dependent manner that correlated with decreased adhesion on BM stromal cells and increased sensitisation of MM cells in the presence of the BM stroma. The Wiskott Aldrich Syndrome Protein (WASP) is an adaptor protein that regulates actin polymerization and organization of cell adhesion molecules of the integrin family in haematopoietic cells. WASP is involved in the signalling pathway downstream of CXCR4 in various leukocytes and we hypothesised that blocking this pathway would prevent MM cell adhesion on stromal cells and sensitise them to treatment with Dexamethasone. We found that downregulation of WASP in the Dexamethasone-sensitive cell line MM1.S using shRNA reduced the adhesion to the BM stroma. However, it also rendered MM1.S cells resistant to treatment with Dexamethasone but not with Bortezomib, Doxorubicin or Melphalan independently of the presence of BM stromal cells. Similarly, downregulation of WASP in MM1.R cells did not affect their sensitivity to Bortezomib, Doxorubicin or Melphalan. Dexamethasone has been shown to induce changes in actin dynamics or in levels or activity of actin and/or adhesion related proteins. Western blot analysis showed both Dexamethasone and Bortezomib to cause modulation of WASP expression, inducing partial downregulation and upregulation, respectively. Downregulation of WASP expression in MM1.S cells using shRNA or treatment with Dexamethasone or Bortezomib did not affect the expression of other proteins involved in WASP-mediated F-actin remodelling or cell adhesion such as WIP, Arp 2/3 or vinculin. We conclude that WASP is involved in the signalling pathways that promote cell-adhesion of MM cells on BM stroma but it is also a vital component of the signalling pathway of Dexamethasone's mechanism of action. These data indicate that while blocking WASP signalling could theoretically have potential therapeutic benefits to prevent CAM-DR to Dexamethasone, it would inhibit the action of Dexamethasone rendering cells resistant to treatment with this drug. Our study suggest a possible paradox of a dual pro-apoptotic and pro-survival effect of certain therapies targeting pathways involved in the interaction of MM cells with the microenvironment. Detailed studies of the intricate connexion between the intracellular pathways involved in the process of adhesion and drug induced cell death through modulation of actin dynamics may lead to improved therapeutic strategies to overcome drug resistance against Dexamethasone and perhaps other drugs. Disclosures: No relevant conflicts of interest to declare.

Wnt3/RhoA/ROCK Signaling Pathway Is Involved in VLA6-Dependent Adhesion-Mediated Drug Resistance of Multiple Myeloma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2518-2518
Author(s):  
Masayoshi Kobune ◽  
Yutaka Kawano ◽  
Rishu Takimoto ◽  
Takuya Matsunaga ◽  
Junji Kato ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Drug Resistance ◽  
Cell Adhesion ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Stromal Cells ◽  
Critical Role ◽  
Rho Kinase ◽  
Myeloma Cell ◽  
Myeloma Cells

Abstract Adhesion of myeloma cells to BM stromal cells is now considered to play a critical role in chemo-resistance. However, little is known about the molecular mechanism of cell adhesion mediated drug resistance (CAM-DR) in multiple myeloma. In this study, we focused on relationship between drug resistance and expression of Wnts, the factor regulating the cell adhesion and proliferation, in myeloma cells. To gain insight into involvement of Wnt signaling in CAM-DR, we first screened the expression of Wnt family in myeloma cell lines (RPMI8226, ARH77, KMS-5 and MM1S) by reverse transcription-polymerase chain reaction analysis. Although the mRNAs of Wnt2b, Wnt7a and Wnt10b were variably expressed in some of myeloma cell lines, Wnt3 mRNA was detected in all the myeloma cells examined. KMS-5 and ARH77, which highly expressed Wnt3 protein, tightly adhered to human BM stromal cells and accumulation of β-catenin and GTP-bounded RhoA was observed in these myeloma cell lines. Conversely, RPMI8226 and MM1S, which modestly expressed Wnt3 protein, rather weakly adhered to human BM stromal cells. We then examined the relevance of Wnt3 expression to adhesive property to stromal cells and to CAM-DR of myeloma cells. KMS-5 and ARH-77 exhibited apparent CAM-DR against Doxorubicin. This CAM-DR was significantly reduced by anti-integrinβ1 antibody, anti- integrinα6 antibody and a Wnt-receptor competitor, secreted Frizzled related protein-1 and Rho kinase inhibitor (Y27632 and OH-fasudil), but not by the specific inhibitor of canonical signaling (DKK-1), indicating that Wnt-mediated CAM-DR which is dependent on integrinα6/β1 (VLA-6)-mediated attachment to stromal cells is induced by Wnt/RhoA-Rho kinase (ROCK) pathway signal. This CAM-DR for doxorubicin was also significantly reduced by Wnt3 siRNA transfer to KMS-5 and further augmented by addition of Wnt3 conditioned medium. These results indicate that Wnt3 contributes to VLA-6-mediated CAM-DR via the Wnt/RhoA/ROCK pathway of myeloma cells. Thus, the Wnt3/RhoA/ROCK signaling pathway could be a promising molecular target to overcome CAM-DR.

scholarly journals Reovirus-induced cell-mediated immunity for the treatment of multiple myeloma within the resistant bone marrow niche

2021 ◽  
Vol 9 (3) ◽  
pp. e001803
Author(s):  
Louise M E Müller ◽  
Gemma Migneco ◽  
Gina B Scott ◽  
Jenny Down ◽  
Sancha King ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
Immune Responses ◽  
Stromal Cells ◽  
Tumor Burden ◽  
Effector Memory ◽  
In Vivo Model ◽  
Bm Niche

BackgroundMultiple myeloma (MM) remains an incurable disease and oncolytic viruses offer a well-tolerated addition to the therapeutic arsenal. Oncolytic reovirus has progressed to phase I clinical trials and its direct lytic potential has been extensively studied. However, to date, the role for reovirus-induced immunotherapy against MM, and the impact of the bone marrow (BM) niche, have not been reported.MethodsThis study used human peripheral blood mononuclear cells from healthy donors and in vitro co-culture of MM cells and BM stromal cells to recapitulate the resistant BM niche. Additionally, the 5TGM1-Kalw/RijHSD immunocompetent in vivo model was used to examine reovirus efficacy and characterize reovirus-induced immune responses in the BM and spleen following intravenous administration. Collectively, these in vitro and in vivo models were used to characterize the development of innate and adaptive antimyeloma immunity following reovirus treatment.ResultsUsing the 5TGM1-Kalw/RijHSD immunocompetent in vivo model we have demonstrated that reovirus reduces both MM tumor burden and myeloma-induced bone disease. Furthermore, detailed immune characterization revealed that reovirus: (i) increased natural killer (NK) cell and CD8+ T cell numbers; (ii) activated NK cells and CD8+ T cells and (iii) upregulated effector-memory CD8+ T cells. Moreover, increased effector-memory CD8+ T cells correlated with decreased tumor burden. Next, we explored the potential for reovirus-induced immunotherapy using human co-culture models to mimic the myeloma-supportive BM niche. MM cells co-cultured with BM stromal cells displayed resistance to reovirus-induced oncolysis and bystander cytokine-killing but remained susceptible to killing by reovirus-activated NK cells and MM-specific cytotoxic T lymphocytes.ConclusionThese data highlight the importance of reovirus-induced immunotherapy for targeting MM cells within the BM niche and suggest that combination with agents which boost antitumor immune responses should be a priority.

scholarly journals Elucidating the expression and function of Numbl during cell adhesion-mediated drug resistance (CAM-DR) in multiple myeloma (MM)

BMC Cancer ◽  
2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Yuejiao Huang ◽  
Xianting Huang ◽  
Chun Cheng ◽  
Xiaohong Xu ◽  
Hong Liu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Multiple Myeloma ◽  
Drug Resistance ◽  
Cell Adhesion ◽  
Cell Lines ◽  
Molecular Mechanisms ◽  
Clinical Problem ◽  
Integrin Β1 ◽  
Cell Viability Assay ◽  
Adhesion Model

Abstract Background Cell adhesion-mediated drug resistance (CAM-DR) is a major clinical problem that prevents successful treatment of multiple myeloma (MM). In particular, the expression levels of integrin β1 and its sub-cellular distribution (internalization and trafficking) are strongly associated with CAM-DR development. Methods Development of an adhesion model of established MM cell lines and detection of Numbl and Integrinβ1 expression by Western Blot analysis. The interaction between Numbl and Integrinβ1 was assessed by a co-immunoprecipitation (CO-IP) method. Calcein AM assay was performed to investigate the levels of cell adhesion. Finally, the extent of CAM-DR in myeloma cells was measured using cell viability assay and flow cytometry analysis. Results Our preliminary date suggest that Numbl is differentially expressed in a cell adhesion model of MM cell lines. In addition to binding to the phosphotyrosine-binding (PTB) domain, the carboxyl terminal of Numbl can also interact with integrin β1 to regulate the cell cycle by activating the pro-survival PI3K/AKT signaling pathway. This study intends to verify and elucidate the interaction between Numbl and integrin β1 and its functional outcome on CAM-DR. We have designed and developed a CAM-DR model using MM cells coated with either fibronectin or bone marrow stromal cells. We assessed whether Numbl influences cell-cycle progression and whether it, in turn, contributes to activation of PI3K/AKT signal pathway through the adjustment of its carboxyl end. Finally, we showed that the interaction of Numbl with integrin β1 promotes the formation of CAM-DR in MM cells. Conclusions Our findings elucidated the specific molecular mechanisms of CAM-DR induction and confirmed that Numbl is crucial for the development of CAM-DR in MM cells.

Abstract 5686: Engineering multifunctional nanoparticles to selectively target multiple myeloma cells and overcome cell adhesion-mediated drug resistance

2012 ◽  
Author(s):  
Tanyel Kiziltepe ◽  
Jonathan D. Ashley ◽  
Jared F. Stefanick ◽  
Nathan J. Alves ◽  
Micheal W. Handlogten ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Drug Resistance ◽  
Cell Adhesion ◽  
Multifunctional Nanoparticles ◽  
Myeloma Cells

CD56 Expression Is the Potent Prognostic Marker of the Thalidomide Efficacy in the Patients with Multiple Myeloma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5142-5142
Author(s):  
Akio Mori ◽  
Yutaka Tsutsumi ◽  
Satoshi Hashino ◽  
Hiroe Kanamori ◽  
Makoto Ibata ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Cell Adhesion ◽  
Adhesion Molecules ◽  
Prognostic Marker ◽  
Stromal Cells ◽  
Bone Marrow Stromal Cells ◽  
Marrow Stromal Cells ◽  
Myeloma Cells ◽  
Cd56 Expression

Abstract Thalidomide (Thal) alone or in combination with steroids achieves responses even in the setting of refractory multiple myeloma (MM), however, responses are still limited. The precise mechanism of Thal action is unknown, further, no distinct marker, which could prognosticate the efficacy of Thal, is known. Therefore, we evaluated the correlation between the efficacy of Thal and the potent prognostic factors in patients with refractory MM. Ten patients with refractory MM received Thal at doses of 50 or 100 mg per day and steroids, either dexamethasone (Dex) or prednisolone (PSL). Dex was administrated 20 mg per day, 4 days every 28 days, and PSL was administrated 10 mg per day. The median age was 71.5 years (range, 62–79 years) and 20 % were man, and all patients were diagnosed as clinical stage IIIA based on the Durie and Salmon classification. The therapeutic response was assessed according to the modified criteria of Southwest Oncology Group (SWOG). Among 10 patients, 7 patients were the responders; 2 had complete remission, 3 had partial remission, and 2 had minimal remission. There were no differences in the pretreatment characteristics of responders and nonresponders (age, sex, type and concentration of serum and/or urine monoclonal component, international prognostic index, presence of bone lesion, and chromosomal abnormalities). However, flow cytometric evaluation of the myeloma cells revealed that CD56, which is one of the adhesion molecules N-CAM, expressed more than 45 % in all responders, while those expressed less than 5 % in all nonresponders (84 ± 19 (±SD) % v/s 4 ± 2 %, P=0.017). Furthermore, CD56 expression of the myeloma cells was reduced from 84% to 70 ± 32 % after Thal therapy in all evaluated responders (P =0.048). These results suggest that CD56 expression of the myeloma cells could be the potent prognostic marker of the Thal efficacy. Moreover, it was reported that Thal reduced the expression of cell adhesion molecules, such as LFA-1 and ICAM-1, and abrogated the binding of MM cells to bone marrow stromal cells, that triggered the secretion of interleukin-6 and vascular endothelial growth factor. Taken together, it was suggested that Thal reduced the expression of CD56 and altered the MM cell adhesion to bone marrow stromal cells, and that could be one of the pathogenesis of anti-MM activity of Thal.

Standardizing Co-Culture Conditions Between Chronic Lymphocytic Leukemia Cells and Marrow Stromal Cells: Towards a Reliable and Reproducible System to Assess Cell Adhesion-Mediated Drug Resistance

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3149-3149
Author(s):  
Antonina Kurtova ◽  
Maite P. Quiroga ◽  
William G. Wierda ◽  
Michael Keating ◽  
Jan A. Burger
Keyword(s):  
Bone Marrow ◽  
Drug Resistance ◽  
Cell Adhesion ◽  
Chronic Lymphocytic Leukemia ◽  
Stromal Cells ◽  
Lymphocytic Leukemia ◽  
Marrow Stromal Cells ◽  
Hpv E6 ◽  
Induced Apoptosis

Abstract Contact between chronic lymphocytic leukemia (CLL) cells and accessory stromal cells in tissue microenvironments is considered to play a major role in regulating CLL cell survival and disease progression. Stromal cells of various origins and species, and variable stromal-CLL cell ratios have been used in the past to study CLL-stromal cell interactions and to assess cell-adhesion mediated drug resistance (CAM-DR). Because of the heterogeneity of the currently used in vitro systems to study CLL-MSC interactions, and the importance of these co-culture systems for development and testing of novel agents, we tested a panel of murine and human MSC lines for their capacities to support CLL cell survival and CAM-DR, using various CLL-MSC ratios and fludarabine (F-ara-A) to induce CLL cell apoptosis. We tested four murine, non-transformed MSC lines derived from bone marrow: M210B4, KUM4, ST-2 and KUSA-H1. Also, we tested three human transformed cell lines: Stroma-NKtert, derived from bone marrow and immortalized by human telomerase reverse transcriptase (hTERT), UE6E7-T2 derived from bone marrow and transformed with human papilloma viruses (HPV) E6, E7 and hTERT, and UCB408E6E7Tert33 derived from umbilical cord blood and transformed with hTERT and HPV E6, E7. CLL cells were isolated from peripheral blood of untreated patients and each cell line was tested with at least three different patients according to the following protocol: viability of CLL was tested after 24, 48 and 72 hours by flow cytometry after staining with DiOC6 and propidium iodide. The following conditions were assayed on each of the MSC lines: CLL cells in suspension culture, CLL cells in suspension culture with 10 mM F-ara-A, CLL cells in co-culture with MSC, and CLL cells in co-culture with MSC and with 10 mM F-ara-A. Firstly, we performed titration experiments in order to identify the most appropriate ratio between stromal and CLL cells, using CLL-MSC ratios of 5:1, 10:1, 20:1, 50:1 and 100:1. We found a decline in MSC-derived CLL cell protection at the highest ratio of 100:1, suggesting that ratios of 50:1 or lower provide optimal conditions for in vitro assays. Results shown in Table 1 were assayed using a 20:1 ratio and represented relative viabilities when compared to untreated controls (mean±SEM). Regarding the protective effect of different MSC, we found that all MSC lines demonstrated remarkable protection of CLL cells from spontaneous and F-ara-A-induced apoptosis. We also found that stromal cells that had round shape morphology and easily formed confluent monolayer (M210B4, KUSA-H1, Stroma-NKTert) showed more prolonged protective effect in comparison to cell lines with more spindle shaped morphology (ST-2, KUM4, UE6E7-T2). The failure of UE6E7-T2 and UCB408E6E7Tert33 to demonstrate long-term protection of CLL cells could be related to their own sensitivity to F-ara-A. In this comparative study we demonstrated that both murine and human MSC provide substantial and comparable levels of protection from spontaneous and drug-induced apoptosis. CLL:MSC ratios of 50:1 or lower can be considered ideal for co-culture experiments. Further experiments have to be done to determine the levels of MSC-derived protection in a larger series of CLL samples and in different laboratories for validation. Collectively, in these co-culture assays we can study CLL-MSC interactions and CLL drugs under more standardized conditions that may allow us to evaluate the efficacy of new treatments that target the CLL microenvironment. Time points 24 hours 48 hours 72 hours +Flu + MSC + MSC +Flu +Flu + MSC + MSC +Flu +Flu +MSC + MSC +Flu M210B4 85.2±2.4 117.2±5.0 110.5±4.9 30.8±12.6 138.1±9.5 113.0±2.2 5.2±3.1 138.1±5.1 120.4±3.4 ST-2 93.6±3.0 99.9±2.6 103.1±0.5 51.6±9.4 111.9±2.6 89.8±8.7 13.9±6.3 112.6±5.7 87.0±16.4 KUM-4 93.6±3.0 106.4±1.8 104.2±1.9 51.6±9.4 112.4±2.6 100.8±2.8 13.9±6.3 111.8±6.7 88.5±11.4 KUSA-H1 79.4±7.4 125.1±3.7 118.2±2.0 33.9±10.9 136.0±3.6 107.2±7.0 11.3±6.1 133.6±5.4 84.9±7.6 Stroma-NKTert 79.3±7.0 118.6±7.0 111.0±7.0 30.5±9.5 130.7±9.5 115.6±8.0 7.1±4.3 133.0±11.5 122.7±9.0 UE6E7-T2 79.3±7.0 113.4±3.9 109.3±3.0 30.5±9.5 118.4±4.8 85.0±7.1 7.1±4.3 119.2±6.9 51.0±10.1 UCB408 E6E7Tert33 81.5±7.2 120.2±5.4 111.8±2.7 36.7±9.4 123.7±6.3 86.7±7.7 8.5±6.7 119.7±6.1 50.8±13.0 Table 1. Flu: fludarabine (10mM/ml), MSC: marrow stromal cells

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