1. ¹Institute of Pharmaceutical Biology / ZAFES / DCAL, JWG-University Frankfurt, Biocenter, Frankfurt/Main, Germany
2. ²Charité, Universitätsmedizin Berlin, Campus Benjamin Franklin, Medizinische Klinik III, Hindenburgdamm 30, Berlin, Germany
3. ³Center of Pediatric Hematology Oncology, University of Catania, Catania, Italy
4. ⁴Department of Immunology, Erasmus MC, Rotterdam, The Netherlands
5. ⁵Department of Haematology, INSERM U563, Hôpital Purpan, Toulouse, France
6. ⁶ZKI, Medical Faculty III, JWG-University Frankfurt, Frankfurt/Main, Germany

Correspondence: Professor Dr R Marschalek, Institute of Pharmaceutical Biology / ZAFES, University of Frankfurt, Marie-Curie Str. 9, 60439 Frankfurt/Main, Germany. E-mail: Rolf.Marschalek@em.uni-frankfurt.de

Received 6 March 2007; Accepted 7 March 2007; Published online 5 April 2007.

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, MLLAF4 and AF4MLL, respectively. By contrast, 20% of all t(4;11) patients seem to encode only the MLLAF4 fusion allele. Here, we analyzed these 'MLLAF4⁺/AF4MLL^-' 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-KB1 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.