The DSMZ cell lines bank holds eight hundred immortalized cell lines. Immortalization can be brought about in vitro, e.g. by genetic manipulation of the cells or by viral infection. Alternatively, immortalization can result from malignant transformation of single cells in vivo.
Oncogenes and tumor suppressor genes are the molecular targets of genetic and epigenetic alterations determining the aberrant character of tumor cells. Cell lines conserve the genetic aberrations causing tumorigenesis. This is the reason why – over decades – cell lines have been used to identify new oncogenes and tumor suppressor genes. Moreover, cell lines are being applied as model systems to study the function of mutated genes, providing the basis for the discovery of new drugs for personalized therapy.
Tumors often show cellular heterogeneity at the chromosomal, genetic and epigenetic level. It has been suggested that in accordance with the Darwinian evolution, malignant clones evolve under the influence of selective forces fueled by mutational alterations. Thereby, therapeutic drugs can be looked upon as one form of selective pressure: efficiently killing the predominant tumor population, therapeutics may be less effective on subclones with other lesions. This may explain why relapsed clones are often genetically distinct from primary diagnostic clones. These observations also explain why “clonal evolution” is currently such an important topic in cancer and in particular leukemia research.
In the last years, we have been able to show that cell lines can retain subclones present in the original tumor. Our current scientific aim is to find out how often cell lines consist of subclones and whether and how clone-specific genetic and epigenetic aberrations affect the tumor cell. The project aims to broaden our view on cell lines showing that cell lines like primary tumors display genetic heterogeneity. Isogenic subclones with small sets of contrasting aberrations facilitate the functional analysis of the mutated genes.
- Quentmeier H, Pommerenke C, Bernhart SH, Dirks WG, Hauer V, Hoffmann S, Nagel S, Siebert R, Uphoff CC, Zaborski M, Drexler HG. ICGC MMML-Seq Consortium. RBFOX2 and alternative splicing in B-cell lymphoma. Blood Cancer Journal 8(8):77 (2018).
- Quentmeier H, Drexler HG, Hauer V, MacLeod RAF, Pommerenke C, Zaborski M, Berglund M, Enblad G, Amini RM. Novel diffuse large B cell lymphoma cell line U-2946: model for MCL1 inhibitor testing. PloSOne 11: e0167599 (2016).
- Quentmeier H, Pommerenke C, Ammerpohl O, Geffers R, Rosati E, Rosén A, Hauer V, MacLeod RAF, Nagel S, Zaborski M, Drexler HG. Subclones in B-lymphoma cell lines: isogenic models for the study of gene regulation. Oncotarget 7:63456-63465 (2016).
- Pommerenke C, Hauer V, Zaborski M, MacLeod RAF, Nagel S, Amini RM, Berglund M, Geffers R, Drexler HG, Quentmeier H. Chr. 11q23 aberrations activating FOXR1 in B-cell lymphoma. Blood Cancer Journal 6:e433. (2016).
- Ding J, Dirks WG, Ehrentraut S, Geffers R, MacLeod RAF, Nagel S, Pommerenke C, Romani J, Scherr M, Vaas LAI, Zaborski M, Drexler HG, Quentmeier H. BCL6 – regulated by AhR/ARNT and wild-type MEF2B – drives expression of germinal center markers MYBL1 and LMO2. Haematologica 100:801-809 (2015).
- Ding J, Romani J, Zaborski M, MacLeod RAF, Nagel S, Drexler HG, Quentmeier H. Inhibition of PI3K/mTOR overcomes nilotinib resistance in BCR-ABL1 positive leukemia cells through translational down-regulation of MDM2. PLoS ONE 8(12): e83510 (2013).
- Quentmeier H, Amini RM, Berglund M, Dirks WG, Ehrentraut S, Geffers R, MacLeod RAF, Nagel S, Romani J, Scherr M, Zaborski M, Drexler HG. U-2932: two clones in one cell line – a tool for the study of clonal evolution. Leukemia 27:1155-1164 (2013).