Human B-cell cancer cell lines as a preclinical model for studies of drug effect in diffuse large B-cell lymphoma and multiple myeloma

Laursen, Maria Bach; Falgreen, Steffen; Bødker, Julie Støve; Schmitz, Alexander; Kjeldsen, Malene Krag; Sørensen, Susanne; Madsen, Jesper; El‐Galaly, Tarec Christoffer; Bøgsted, Martin; Dybkær, Karen; Johnsen, Hans Erik

doi:10.1016/j.exphem.2014.07.263

Cited by 16 publications

(23 citation statements)

References 66 publications

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“…As shown in Fig. 1B, EZH2 wild-type cell lines with canonical ABC mutations like OCI-LY3 (MYD88), TMD8 (CD79B) display similar sensitivity to tazemetostat with EZH2 wild-type cell lines of GCB origin like Farage, OCI-LY7, or SU-DHL-5 (35). When comparing mutant and wild-type cell lines at identical concentrations of inhibitor, we observe that the EZH2-mutant cell line, KARPAS-422, shows a strong cytotoxic response at 250 nmol/L tazemetostat while cell lines with wild-type EZH2, like SU-DHL-5 (GCB), Farage (GCB), and TMD8 (ABC) show dose-dependent decreases in proliferation (Fig.…”

Section: Effects Of Tazemetostat In Wild-type Versus Mutant Ezh2 Cellmentioning

confidence: 78%

EZH2 Inhibition by Tazemetostat Results in Altered Dependency on B-cell Activation Signaling in DLBCL

Brach

Johnston-Blackwell

Drew

et al. 2017

Molecular Cancer Therapeutics

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The EZH2 small-molecule inhibitor tazemetostat (EPZ-6438) is currently being evaluated in phase II clinical trials for the treatment of non-Hodgkin lymphoma (NHL). We have previously shown that EZH2 inhibitors display an antiproliferative effect in multiple preclinical models of NHL, and that models bearing gain-of-function mutations in EZH2 were consistently more sensitive to EZH2 inhibition than lymphomas with wild-type (WT) EZH2. Here, we demonstrate that cell lines bearing EZH2 mutations show a cytotoxic response, while cell lines with WT-EZH2 show a cytostatic response and only tumor growth inhibition without regression in a xenograft model. Previous work has demonstrated that cotreatment with tazemetostat and glucocorticoid receptor agonists lead to a synergistic antiproliferative effect in both mutant and wild-type backgrounds, which may provide clues to the mechanism of action of EZH2 inhibition in WT-EZH2 models. Multiple agents that inhibit the B-cell receptor pathway (e.g., ibrutinib) were found to have synergistic benefit when combined with tazemetostat in both mutant and WT-EZH2 backgrounds of diffuse large B-cell lymphomas (DLBCL). The relationship between B-cell activation and EZH2 inhibition is consistent with the proposed role of EZH2 in B-cell maturation. To further support this, we observe that cell lines treated with tazemetostat show an increase in the B-cell maturation regulator, PRDM1/BLIMP1, and gene signatures corresponding to more advanced stages of maturation. These findings suggest that EZH2 inhibition in both mutant and wild-type backgrounds leads to increased Bcell maturation and a greater dependence on B-cell activation signaling.

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Section: Effects Of Tazemetostat In Wild-type Versus Mutant Ezh2 Cellmentioning

confidence: 78%

EZH2 Inhibition by Tazemetostat Results in Altered Dependency on B-cell Activation Signaling in DLBCL

Brach

Johnston-Blackwell

Drew

et al. 2017

Molecular Cancer Therapeutics

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“…B) Applying the same set of marker genes, cell line U-2946 clustered together with described ABC DLBCL cell lines (red), not with GC cell lines (green) [5–9]. Cell line NU-DHL-1 (orange) was discordantly categorized by different authors [6,8]. We showed that subclone R1 of the ABC cell line U-2932 highly expressed various GC markers, absent from subclone R2 [34].…”

Section: Resultsmentioning

confidence: 99%

Diffuse Large B Cell Lymphoma Cell Line U-2946: Model for MCL1 Inhibitor Testing

et al. 2016

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Diffuse large B cell lymphoma (DLBCL) is the most common form of non-Hodgkin lymphoma worldwide. We describe the establishment and molecular characteristics of the DLBCL cell line U-2946. This cell line was derived from a 52-year-old male with DLBCL. U-2946 cells carried the chromosomal translocation t(8;14) and strongly expressed MYC, but not the mature B-cell lymphoma associated oncogenes BCL2 and BCL6. Instead, U-2946 cells expressed the antiapoptotic BCL2 family member MCL1 which was highly amplified genomically (14n). MCL1 amplification is recurrent in DLBCL, especially in the activated B cell (ABC) variant. Results of microarray expression cluster analysis placed U-2946 together with ABC-, but apart from germinal center (GC)-type DLBCL cell lines. The 1q21.3 region including MCL1 was focally coamplified with a short region of 17p11.2 (also present at 14n). The MCL1 inhibitor A-1210477 triggered apoptosis in U-2946 (MCL1pos/BCL2neg) cells. In contrast to BCL2pos DLBCL cell lines, U-2946 did not respond to the BCL2 inhibitor ABT-263. In conclusion, the novel characteristics of cell line U-2946 renders it a unique model system to test the function of small molecule inhibitors, especially when constructing a panel of DLBCL cell lines expressing broad combinations of antiapoptotic BCL2-family members.

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“…During the last decade, MSCNET has performed detailed studies to confirm or refute previous studies [47][48][49][50][51][52][53][54][55][56][57][58][59][60] and established protocols 17,[61][62][63][64][65][66][67][68][69][70] to delineate the phenotypes of subpopulations of cells in randomly selected primary tumor samples and in preclinical disease models. While our investigations did not confirm that pre-PC B cells are myeloma initiating, 50 low/-memory B cells engrafted into human bone grafts, resulting in the repopulation of polyclonal B cells, which supports the hypothesis that memory B cells have the ability to self-renew.…”

Section: In Search Of the Mmscmentioning

confidence: 99%

“…Plasticity in MM is perhaps best illustrated by the subtyping of clinical tumor samples based on B-cell subset-associated gene signatures; tumors previously assigned to PreB-II and memory-cell subtypes of malignant PCs were associated with inferior prognoses. [57][58][59][60] This observation provides a new tool for generating insight into the stages of clonal plasticity associated with oncogenesis and deregulated differentiation. The mechanisms of myelomacell plasticity should be exploited, and their significance for the concept of MMSCs assessed.…”

mentioning

confidence: 97%

“…We have taken the first step toward defining gene signatures of drug-specific resistance in pre-clinical models of HMCL. [57][58][59][60] Self-renewal, plasticity, and resistance have been studied in the preclinical model of HMCL, which is considered to be the most advanced and homogenous myeloma tissue available. It is important to recognize that each HMCL reflects the end stage of an individual patient's genetic evolution and selection, but each HMCL also reflects the aggregation of stepwise oncogenic events over time, some of which may have deregulated the hallmarks of MMSCs.…”

mentioning

confidence: 99%

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The myeloma stem cell concept, revisited: from phenomenology to operational terms

et al. 2016

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Human B-cell cancer cell lines as a preclinical model for studies of drug effect in diffuse large B-cell lymphoma and multiple myeloma

Cited by 16 publications

References 66 publications

EZH2 Inhibition by Tazemetostat Results in Altered Dependency on B-cell Activation Signaling in DLBCL

EZH2 Inhibition by Tazemetostat Results in Altered Dependency on B-cell Activation Signaling in DLBCL

Diffuse Large B Cell Lymphoma Cell Line U-2946: Model for MCL1 Inhibitor Testing

The myeloma stem cell concept, revisited: from phenomenology to operational terms

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