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Establishment of an inducible expression system of chimeric MLL-LTG9 protein and inhibition of Hox a7, Hox b7 and Hox c9 expression by MLL-LTG9 in 32Dcl3 cells

Oncogene volume 18, pages 1125–1130 (1999)Cite this article

Abstract

The MLL (HRX/ALL-1 gene is frequently disrupted in infantile leukemias and therapy-related leukemias and fused to various translocation partner genes. We previously showed that chimeric MLL proteins localize in the nuclei in a fashion similar to that of MLL protein even if the partner gene encodes a cytoplasmic protein and indicated the importance of the N-terminal portion of MLL common to various MLL translocations. This time we established an inducible expression system for chimeric MLL-LTG9 and truncated N-terminal MLL proteins (MLL-Zf(−)) in 32Dcl3 cells. By utilizing this system, we were able to show inhibition of Hox a7, Hox b7 and Hox c9 genes' expression by induced MLL-LTG9 and MLL-Zf(−). Up-regulation of Hox a7, Hox b7 and Hox c9 was observed when 32Dcl3 cells were cultured with granulocyte colony stimulating factor (G-CSF) in place of interleukin 3 and induction of MLL-LTG9 and MLL-Zf(−) was shown to suppress this up-regulation. At the same time, expression of two mammalian Polycomb group genes, M33 and mel-18, which both reportedly affect Hox genes' expression, was not inhibited by MLL-LTG9 and MLL-Zf(−) induction. These results indicate that MLL has an important effect on the expression of at least some Hox genes in hematopoietic cells and suggest that inhibition of the proper expression of Hox genes by chimeric MLL proteins may dysregulate hematopoietic cell differentiation and proliferation, which then can lead to leukemogenesis.

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Acknowledgements

We greatly appreciate the technical assistance of Ms K Nishida, Ms H Suzuki and Ms Y Maeda. This work was supported in part by a Grant-in-aid for the Second Term Comprehensive 10-year Strategy for Cancer Control from the Ministry of Health and Welfare, a Grant-in-aid for Science in Primary Areas (Cancer Research), a Grant-in-aid for the Encouragement of Young Scientists from the Ministry of Education, Science and Culture, Japan, a Grant-in-aid from the Uehara Memorial Foundation, and the Bristol-Myers Squibb Unrestricted Biomedical Research Grants Program.

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Authors and Affiliations

  1. Laboratories of Chemotherapy, Aichi Cancer Center Research Institute, Nagoya, 464-8681, Japan

    Tatsuroh Joh, Yoshitaka Hosokawa, Ritsuro Suzuki & Masao Seto

  2. Laboratories of Immunology, Aichi Cancer Center Research Institute, Nagoya, 464-8681, Japan

    Toshitada Takahashi

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  1. Tatsuroh Joh
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Joh, T., Hosokawa, Y., Suzuki, R. et al. Establishment of an inducible expression system of chimeric MLL-LTG9 protein and inhibition of Hox a7, Hox b7 and Hox c9 expression by MLL-LTG9 in 32Dcl3 cells. Oncogene 18, 1125–1130 (1999). https://doi.org/10.1038/sj.onc.1202400

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