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Clonal expansion of non-leukemic cells expressing two novel MLL–ELL variants differing in transforming activity

Leukemia volume 22, pages 861–864 (2008)Cite this article

The mixed lineage leukemia gene (MLL, also known as ALL-1, HTRX-1 or HRX) is one of the major genes involved in gene rearrangements in acute leukemia.1 More than 80 different translocations of the MLL gene have been described and at least 51 partner genes have already been identified.2 The Eleven-nineteen Lysine-rich Leukemia gene (ELL, also known as MEN) located at 19p13.1, one of those partner genes, encodes an RNA polymerase II transcriptional elongation factor that increases the catalytic rate of transcriptional elongation by RNA polymerase II.3 A very poor prognosis has been reported in cases of MLL-associated leukemia including MLL–ELL-associated leukemia. In a murine model, transduction of MLL–ELL in hematopoietic progenitor cells promoted their transformation in vitro and induced leukemia in vivo.4 In all reported cases of MLL–ELL-associated leukemia, exon 10 or 11 of MLL, according to the new exon/intron numbering of Nilson I et al., fused to ELL.3 Here, we present a novel form of MLL–ELL with a breakpoint junction between exon 12 of MLL and exon 2 of ELL, which was identified in a patient who showed a progressive clonal expansion of non-leukemic cells with MLL–ELL, eventually accounting for up to 90% of bone marrow (BM) cells, after a successful induction therapy. A detailed analysis of MLL–ELL transcripts identified two alternatively spliced isoforms generated from the rearranged gene, which differed in their activity to transform myeloid progenitors in vitro.

Although MLL–ELL-positive leukemia usually takes an aggressive clinical course, our patient was in a non-leukemic state for some time. The MLL–ELL-positive cells, which clonally expanded to compete with normal hematopoiesis, lacked trisomy 8 and showed a normal multilineage differentiation ability. To our knowledge, this is the first report of an MLL–ELL-positive clone with a significant growth advantage and normal multilineage differentiation potential. Given that 90.1% of BM cells were positive for the MLL rearrangement without any accumulation of blasts in the BM, the rearrangement supposedly occurred in hematopoietic stem cells, which eventually differentiated and maintained hematopoietic homeostasis without causing overt leukemia. Thus, it is likely that the rearrangement of MLL was not enough to induce overt leukemia and trisomy 8 was required for leukemogenesis in this case. The unusual clinical course of the patient might be attributed to the unique forms of MLL–ELL newly identified here. Sequence analysis revealed that the MLL–ELL clones represented two alternatively spliced isoforms of a novel MLL–ELL variant with a breakpoint junction between exon 12 of MLL and exon 2 of ELL. Of note was that the major isoform, MLL–ELL E11/12, did not exhibit transforming activity in the myeloid progenitor immortalization assay. In contrast, the minor isoform, MLL–ELL E12, exhibited strong activity to transform myeloid progenitor cells in vitro. These results suggest that because the isoform that is ineffective in transforming cells dominated in MLL–ELL-positive cells, they needed to acquire a second factor, trisomy 8 in this case, for leukemic transformation.

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Acknowledgements

We thank Drs MJ Thirman and T Kitamura for providing the common-type MLL–ELL cDNA and pMXs-puro vector, respectively. This work was supported in part by grants from the Ministry of Education, Culture, Sports, Science and Technology, Japan, and Core Research for Evolutional Science and Technology (CREST) of Japan Science and Technology Corporation (JST).

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  1. Division of Hematology, Department of Clinical Cell Biology, Chiba University Graduate School of Medicine, Chiba, Japan

    M Takeuchi, C Nakaseko, Y Takeda, S Ozawa, C Ohwada, R Cho, M Nishimura & Y Saito

  2. Department of Cellular and Molecular Medicine, Chiba University Graduate School of Medicine, Chiba, Japan

    M Takeuchi, S Miyagi & A Iwama

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  1. M Takeuchi
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  2. C Nakaseko
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Correspondence to C Nakaseko.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Takeuchi, M., Nakaseko, C., Miyagi, S. et al. Clonal expansion of non-leukemic cells expressing two novel MLL–ELL variants differing in transforming activity. Leukemia 22, 861–864 (2008). https://doi.org/10.1038/sj.leu.2404954

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