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Research CytogeneticsZytogentik


Figure 1: Nuclei are more than sacks of DNA, and cytogenetics need not just be descriptive. The image shows contrastingly tight and loose attachment of actively transcribed (orange) and silent (green) genes to the nuclear matrix1 in a T-ALL cell line (CCRF-CEM) to illustrate how cytogenetic method - Halo-FISH in this case – may be used in a functional assay.

Cytogenetic research at the DSMZ targets discovery of new – often cryptic – oncogenomic rearrangements in the cell lines collection. These, in turn, enable discovery of cancer genes which may escape detection in clinical samples. It seems that certain - often poor prognosis – rearrangements are over-represented in cell lines, perhaps because they promote cell immortalization. Cell lines bearing neoplastic alterations provide disease models for investigating inter alia the signalling targets of specific gene alterations which may inform therapeutic targeting. The effectiveness and target profiles of “intelligent” small molecule inhibitors may then be tested in context both at survival/proliferation and transcriptional levels. Figure 1 shows how cytogenetic analysis may be used to characterize cancer genes in cell lines (1).

Current projects (performed in collaboration with the Molecular Genetics group) include analysis of chromosome rearrangements targeting activation of micro-RNA (miR) genes in leukemia. Although various miR are known to serve as cancer genes via copy number alterations (see Figure 2), in only one instance hitherto, that of miR-125b in acute lymphoid and myeloid leukemias, is upregulation known to be effected structurally by chromosomal juxtaposition per se, as in conventional oncogene translocations. We have recently documented an example in B-cell lymphoma where miR-17~92 is activated by a concurrent BCL6 chromosome rearrangement leading to hyperacetylation of the miR promoter region, while yet other examples in a variety of hematopoietic tumors are currently under investigation. Other recent or current projects regard new rearrangements involving LMO2 and NOTCH1 in T-ALL (2,3), BCL6 in B-cell lymphoma (4, 5), ETV6 in acute myeloid leukemia and JAK2 in cutaneous lymphoma.

Figure 2: miR-17~92 amplification in Burkitt lymphoma

Parallel to cytogenetic analysis, microarray based genomic analysis may be performed to investigate both copy number changes or map unbalance breakpoints which, together with transcriptional arrays, provide integrative data seldom available in clinical studies.


1. Nagel S, Scherr M, Kel A, Hornischer K, Crawford GE, Kaufmann M, Meyer C, Drexler HG, MacLeod RAF. Activation of TLX3 and NKX2-5 in t(5;14)(q35;q32) T-cell acute lymphoblastic leukemia by remote 3´-BCL11B enhancers and coregulation by PU.1 and HMGA1. Cancer Res: 1461-1471 (2007).

2. Chen S, Nagel S, Schneider B, Kaufmann M, Meyer C, Zaborski M, Kees U, Drexler HG, MacLeod RAF. Novel non-TCR chromosome translocations t(3;11)(q25;p13) and t(X;11)(q25;p13) activating LMO2 by juxtaposition with MBNL1 and STAG2. Leukemia, in press, 2011.

3. Suzuki S, Nagel S, Schneider B, Chen S, Kaufmann M, Uozumi K, Arima N, Drexler HG, MacLeod RAF. A second NOTCH1 chromosome rearrangement: t(9;14)(q34.3;q11). Leukemia 23: 1003-1006 (2009).

4. Schneider B, Nagel S, Kaufmann M, Winkelmann S, Bode J, Drexler HG, MacLeod RAF. t(3;7)(q27;q32) fuses BCL6 to a non-coding region at FRA7H near miR-29. Leukemia 22: 1262-1266 (2008).

5. Schneider B, Nagel S, Ehrentraut S, Kaufmann M, Meyer C, Geffers R, Drexler HG, MacLeod RAF. Neoplastic MiR-17~92 deregulation at a DNA fragility Motif (SIDD). Genes Chromosomes Cancer, in press, 2012.