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Cytogenetics and Molecular Genetics

Complex MLL rearrangements in t(4;11) leukemia patients with absent AF4 · MLL fusion allele

Leukemia volume 21, pages 1232–1238 (2007)Cite this article

Abstract

The human mixed lineage leukemia (MLL) gene is frequently involved in genetic rearrangements with more than 55 different translocation partner genes, all associated with acute leukemia. Reciprocal chromosomal translocations generate two MLL fusion alleles, where 5′- and 3′-portions of MLL are fused to gene segments of given fusion partners. In case of t(4;11) patients, about 80% of all patients exhibit both reciprocal fusion alleles, MLL · AF4 and AF4 · MLL, respectively. By contrast, 20% of all t(4;11) patients seem to encode only the MLL · AF4 fusion allele. Here, we analyzed these ’MLL·AF4+/AF4·MLL−’ patients at the genomic DNA level to unravel their genetic situation. Cryptic translocations and three-way translocations were found in this group of t(4;11) patients. Reciprocal MLL fusions with novel translocation partner genes, for example NF- K B1 and RABGAP1L, were identified and actively transcribed in leukemic cells. In other patients, the reciprocal 3′-MLL gene segment was fused out-of-frame to PBX1, ELF2, DSCAML1 and FXYD6. The latter rearrangements caused haploinsufficiency of genes that are normally expressed in hematopoietic cells. Finally, patients were identified that encode only solitary 3′-MLL gene segments on the reciprocal allele. Based on these data, we propose that all t(4;11) patients exhibit reciprocal MLL alleles, but due to the individual recombination events, provide different pathological disease mechanisms.

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Acknowledgements

This study was supported by grants MA 1876/7-1 from the DFG, N1KR-S12T13 from the BMBF, 2001.061.2 from the Wilhelm-Sander-Foundation, and 102362 from the German Cancer Foundation to R.M. TB was supported by a grant from the Berliner Krebsgesellschaft. TB thanks Professor E. Thiel and Professor D. Hoelzer for their support and Ms. Mara Molkentin for excellent technical assistance.

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Authors and Affiliations

  1. Institute of Pharmaceutical Biology / ZAFES / DCAL, JWG-University Frankfurt, Biocenter, Frankfurt/Main, Germany

    E Kowarz, Theo Dingermann, C Meyer & R Marschalek

  2. Charité, Universitätsmedizin Berlin, Campus Benjamin Franklin, Medizinische Klinik III, Hindenburgdamm 30, Berlin, Germany

    T Burmeister

  3. Center of Pediatric Hematology Oncology, University of Catania, Catania, Italy

    L Lo Nigro

  4. Department of Immunology, Erasmus MC, Rotterdam, The Netherlands

    M W J C Jansen

  5. Department of Haematology, INSERM U563, Hôpital Purpan, Toulouse, France

    E Delabesse

  6. ZKI, Medical Faculty III, JWG-University Frankfurt, Frankfurt/Main, Germany

    T Klingebiel

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  1. E Kowarz
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Correspondence to R Marschalek.

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Kowarz, E., Burmeister, T., Lo Nigro, L. et al. Complex MLL rearrangements in t(4;11) leukemia patients with absent AF4 · MLL fusion allele. Leukemia 21, 1232–1238 (2007). https://doi.org/10.1038/sj.leu.2404686

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