Malignant hematopoietic cell lines:<i>in vitro</i>models for double-hit B-cell lymphomas

Drexler, Hans; Eberth, Sonja; Nagel, Stefan; MacLeod, Roderick A.F.

doi:10.3109/10428194.2015.1108414

Cited by 25 publications

(26 citation statements)

References 45 publications

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“…The information on BCL2 and MYC translocation reported in Fig. 2B was obtained from either American Type Culture Collection (www.lgcstandards-atcc.org/Products/Cells_and_Microorganisms/ Cell_Lines/Human.aspx) or DSMZ (Deutsche Sammlung von Mikroorganismen und Zellkulturen, www.dsmz.de/catalogues/catalogue-humanand-animal-cell-lines.html) (62). Tigecycline, doxorubicin, and venetoclax (all from Carbosynth) were dissolved in dimethyl sulfoxide and added directly to the culture medium.…”

Section: Cell Linesmentioning

confidence: 99%

Therapeutic synergy between tigecycline and venetoclax in a preclinical model of MYC / BCL2 double-hit B cell lymphoma

et al. 2018

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High-grade B cell lymphomas with concurrent activation of the and oncogenes, also known as double-hit lymphomas (DHL), show dismal prognosis with current therapies. activation sensitizes cells to inhibition of mitochondrial translation by the antibiotic tigecycline, and treatment with this compound provides a therapeutic window in a mouse model of-driven lymphoma. We now addressed the utility of this antibiotic for treatment of DHL. activation in mouse Eμ- lymphomas antagonized tigecycline-induced cell death, which was specifically restored by combined treatment with the BCL2 inhibitor venetoclax. In line with these findings, tigecycline and two related antibiotics, tetracycline and doxycycline, synergized with venetoclax in killing human DHL cells. Treatment of mice engrafted with either DHL cell lines or a patient-derived xenograft revealed strong antitumoral effects of the tigecycline/venetoclax combination, including long-term tumor eradication with one of the cell lines. This drug combination also had the potential to cooperate with rituximab, a component of current front-line regimens. Venetoclax and tigecycline are currently in the clinic with distinct indications: Our preclinical results warrant the repurposing of these drugs for combinatorial treatment of DHL.

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Section: Cell Linesmentioning

confidence: 99%

Therapeutic synergy between tigecycline and venetoclax in a preclinical model of MYC / BCL2 double-hit B cell lymphoma

et al. 2018

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“…These aberrations can occur in the same tumors, which are then called “double-hit” or “triple-hit” lymphoma according to their aberration scores. Cell lines representing double-hit and triple-hit lymphomas have recently been reviewed in detail [35]. Amplifications or canonical translocations affecting chromosomes 18q21 ( BCL2 ), 3q27 ( BCL6 ) were not detected in U-2946 cells.…”

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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“…A summary of the in vitro data is , and/or BCL6 rearrangements, 18 indicated by an asterisk in Figure 1, were among the cells that showed high sensitivity to SGN-CD19B. We did not see a strong correlation between CD19 expression levels and IC 50 values for SGN-CD19B (supplemental Figure 1, available on the Blood Web site).…”

Section: B Cellsmentioning

confidence: 85%

“…Unique symbols denote tumor type or subtype. Double-hit or triple-hit lymphoma cell lines, as reported in the literature, 18 are indicated on the x-axis using an asterisk.…”

Section: Sgn-cd19b Activity In Vivomentioning

confidence: 99%

Therapeutic potential of SGN-CD19B, a PBD-based anti-CD19 drug conjugate, for treatment of B-cell malignancies

Ryan¹,

Palanca-Wessels

Schimpf³

et al. 2017

Blood

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• SGN-CD19B is broadly active in vitro against malignant B-cell lines, including doublehit and triple-hit lymphoma cell lines.• SGN-CD19B shows significant antitumor activity in vivo in preclinical models of B-NHL and B-cell-derived acute lymphoblastic leukemia.Patients with relapsed/refractory B-cell malignancies such as non-Hodgkin lymphoma (B-NHL) or acute lymphoblastic leukemia have a poor prognosis. Despite measurable clinical activity with new targeted therapies, many patients do not achieve a complete or durable response suggesting an opportunity to improve upon existing therapies. Here we describe SGN-CD19B, a pyrrolobenzodiazepine (PBD)-based anti-CD19 antibody drug conjugate (ADC) being investigated for treatment of B-cell malignancies, which has improved potency compared with other ADCs. CD19-expressing tumor cells rapidly internalize SGN-CD19B, and the released PBD drug induces DNA damage, resulting in G2/M cell cycle arrest and cell death. SGN-CD19B demonstrated activity against a broad panel of malignant B-cell lines and induced durable regressions in mice bearing xenografts derived from these B-cell malignancies. A single dose of SGN-CD19B induced durable regressions at 300 mg/kg (3 mg/kg drug equivalents); combination with rituximab decreased the curative dose to 100 mg/kg (1 mg/kg drug equivalents). These doses are significantly lower than the level of drug required with other ADC payloads. In cynomolgus monkeys, SGN-CD19B effectively depleted CD20 1 B lymphocytes in peripheral blood and lymphoid tissues confirming that SGN-CD19B is pharmacodynamically active at well-tolerated doses. In summary, preclinical studies show SGN-CD19B is a highly active ADC, which releases a DNA cross-linking agent rather than a microtubule inhibitor. The distinct mechanism of action, broad potency, and potential to combine with rituximab suggest that SGN-CD19B may offer unique clinical opportunities in B-cell malignancies. A phase 1 clinical trial is in progress to investigate the therapeutic potential of SGN-CD19B in relapsed/refractory B-NHL.

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Malignant hematopoietic cell lines:in vitromodels for double-hit B-cell lymphomas

Cited by 25 publications

References 45 publications

Therapeutic synergy between tigecycline and venetoclax in a preclinical model of MYC / BCL2 double-hit B cell lymphoma

Therapeutic synergy between tigecycline and venetoclax in a preclinical model of MYC / BCL2 double-hit B cell lymphoma

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

Therapeutic potential of SGN-CD19B, a PBD-based anti-CD19 drug conjugate, for treatment of B-cell malignancies

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