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

Hilmar Quentmeier,Claudia Pommerenke,Hans G Drexler,Vivien Hauer,Margarete Zaborski,Mattias Berglund,Cord C Uphoff,Roderick A F Macleod,Rose-Marie Amini,Gunilla Enblad

doi:10.1371/journal.pone.0167599

Abstract

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.

Highlights

Continuous cell lines have become indispensable tools in leukemia/lymphoma research
We propose U-2946 as auspicious model cell line which shows the rare combination of MCL1 positivity and BCL2 negativity
We describe the establishment and characteristics of the Diffuse large B cell lymphoma (DLBCL) cell line U-2946

Summary

Introduction

Continuous cell lines have become indispensable tools in leukemia/lymphoma research. Self -renewing and transportable in the frozen state, cell lines provide unlimited supplies of cellular tumor material worldwide. Descendent from single cells of a patients tumor, they retain oncogenomic aberrations and gene expression patterns characteristic of the primary tumor. Tumor congruence is a key reason why cell lines are used as models to study the function of aberrantly expressed genes or to test the efficiency of novel anti-cancer drugs [1,2]. Various genes are recurrently affected by mutations and chromosomal aberrations therein, including the germinal center oncogenes BCL2, BCL6 and MYC [3]. Expression array analysis has identified two molecularly distinct forms of the tumor, termed germinal center (GC) and PLOS ONE | DOI:10.1371/journal.pone.0167599. Expression array analysis has identified two molecularly distinct forms of the tumor, termed germinal center (GC) and PLOS ONE | DOI:10.1371/journal.pone.0167599 December 1, 2016

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