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Variable responses of MYC translocation positive lymphoma cell lines to different combinations of novel agents: Impact of BCL2 family protein expression

Variable responses of MYC translocation positive lymphoma cell lines to different combinations of novel agents: Impact of BCL2 family protein expression
Variable responses of MYC translocation positive lymphoma cell lines to different combinations of novel agents: Impact of BCL2 family protein expression
Several newly developed drugs including JQ1 (BET inhibitor), ABT199 (BCL2 inhibitor), and bortezomib (proteasome inhibitor) may offer novel therapeutic strategies for aggressive diffuse large B-cell lymphoma (DLBCL). We tested these drugs together with doxorubicin in a series of combinations in 16 DLBCL cell lines including 4 ABC-DLBCL (OCI-Ly3, OCI-Ly10, SUDHL2, RIVA) and 12 GCB-DLBCL lines (OCI-Ly4, OCI-Ly18, BJAB, SUDHL4, SUDHL6, SUDHL10, DB, PR1, VAL, SC1, Karpas-231, Karpas-422). Among these cell lines, ABT199 and doxorubicin, and to a lesser extent JQ1 and bortezomib, showed high variations in their ED50 values. Of the six cell lines showing high ABT199 ED50 values, four (SUDHL10, OCI-Ly4, SUDHL2, and BJAB) had no or little BCL2 expression, and SUDHL6 also displayed a low BCL2 expression. There was no association between the ED50 value of doxorubicin, JQ1 and bortezomib, and TP53/MYC/BCL2 genetic abnormalities or cell of origin subtype. A synergistic effect in all or the majority of drug combinations was seen in 11 cell lines, while an antagonistic effect in a high proportion of drug combinations was observed in the remaining 5 cell lines including the 3 (SUDHL10, OCI-Ly4, and SUDHL2) with little BCL2 expression, and additionally OCI-Ly18 and RIVA. Extensive Western blot analyses revealed high MCL1 expression in SUDHL10 and OCI-Ly4 but no apparent alterations in other cell lines. The molecular mechanism underlying the antagonistic effect of drug combinations in DLBCL is heterogeneous with the altered BCL2 family protein expression (absent BCL2, but high MCL1) in some cell lines.
1147-1154
Johnson, Peter
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Deng, Wenhan
435541db-9dbd-481b-8290-901c1b9a400d
Clipson, Alexandra
4ca214f4-85ea-40b2-85bb-d0931ccc44ae
Liu, Hongxiang
134bc012-1df6-41f4-96b2-dc70a3c11cae
Huang, Yuanxue
e3c6c48c-404a-459b-b7db-6aa171da0b45
Dobson, Rachel
fe6988d1-45ee-435f-bc77-5ec3e439d0e3
Wang, Ming
b00cdabd-cf02-4ac5-9dfa-440dc1834e2b
Du, Ming-Qing
e5958a4b-4cae-4ed3-acab-f79da2ed4071
Johnson, Peter
3f6068ce-171e-4c2c-aca9-dc9b6a37413f
Deng, Wenhan
435541db-9dbd-481b-8290-901c1b9a400d
Clipson, Alexandra
4ca214f4-85ea-40b2-85bb-d0931ccc44ae
Liu, Hongxiang
134bc012-1df6-41f4-96b2-dc70a3c11cae
Huang, Yuanxue
e3c6c48c-404a-459b-b7db-6aa171da0b45
Dobson, Rachel
fe6988d1-45ee-435f-bc77-5ec3e439d0e3
Wang, Ming
b00cdabd-cf02-4ac5-9dfa-440dc1834e2b
Du, Ming-Qing
e5958a4b-4cae-4ed3-acab-f79da2ed4071

Johnson, Peter, Deng, Wenhan, Clipson, Alexandra, Liu, Hongxiang, Huang, Yuanxue, Dobson, Rachel, Wang, Ming and Du, Ming-Qing (2018) Variable responses of MYC translocation positive lymphoma cell lines to different combinations of novel agents: Impact of BCL2 family protein expression. Translational Oncology, 11 (5), 1147-1154. (doi:10.1016/j.tranon.2018.07.007).

Record type: Article

Abstract

Several newly developed drugs including JQ1 (BET inhibitor), ABT199 (BCL2 inhibitor), and bortezomib (proteasome inhibitor) may offer novel therapeutic strategies for aggressive diffuse large B-cell lymphoma (DLBCL). We tested these drugs together with doxorubicin in a series of combinations in 16 DLBCL cell lines including 4 ABC-DLBCL (OCI-Ly3, OCI-Ly10, SUDHL2, RIVA) and 12 GCB-DLBCL lines (OCI-Ly4, OCI-Ly18, BJAB, SUDHL4, SUDHL6, SUDHL10, DB, PR1, VAL, SC1, Karpas-231, Karpas-422). Among these cell lines, ABT199 and doxorubicin, and to a lesser extent JQ1 and bortezomib, showed high variations in their ED50 values. Of the six cell lines showing high ABT199 ED50 values, four (SUDHL10, OCI-Ly4, SUDHL2, and BJAB) had no or little BCL2 expression, and SUDHL6 also displayed a low BCL2 expression. There was no association between the ED50 value of doxorubicin, JQ1 and bortezomib, and TP53/MYC/BCL2 genetic abnormalities or cell of origin subtype. A synergistic effect in all or the majority of drug combinations was seen in 11 cell lines, while an antagonistic effect in a high proportion of drug combinations was observed in the remaining 5 cell lines including the 3 (SUDHL10, OCI-Ly4, and SUDHL2) with little BCL2 expression, and additionally OCI-Ly18 and RIVA. Extensive Western blot analyses revealed high MCL1 expression in SUDHL10 and OCI-Ly4 but no apparent alterations in other cell lines. The molecular mechanism underlying the antagonistic effect of drug combinations in DLBCL is heterogeneous with the altered BCL2 family protein expression (absent BCL2, but high MCL1) in some cell lines.

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Accepted/In Press date: 10 July 2018
e-pub ahead of print date: 25 July 2018
Published date: October 2018

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Local EPrints ID: 422730
URI: https://eprints.soton.ac.uk/id/eprint/422730
PURE UUID: 22680734-f091-4724-b6ac-6d9ba35acd4c
ORCID for Peter Johnson: ORCID iD orcid.org/0000-0003-2306-4974

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Date deposited: 01 Aug 2018 16:30
Last modified: 14 Mar 2019 01:49

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