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Acute Lymphoblastic Leukemia: MLL-AF4 and Cell Cycle

Modulation of cell cycle by graded expression of MLL-AF4 fusion oncoprotein

Leukemia volume 18, pages 1064–1071 (2004)Cite this article

Abstract

Acute lymphoblastic leukemia (ALLs) expressing MLL-AF4, the fusion product of t(4;11)(q21;q23), show marked leucocytosis and extramedullary disease in multiple organs, respond poorly to chemotherapy and have poor prognosis. In vitro, leukemic cells with the t(4;11) show resistance to serum deprivation-induced or interferon γ-regulated CD95-mediated apoptosis. In addition, t(4;11) cells have prolonged doubling time and lower percentage of cells in cycle compared to non-t(4;11) B lineage cell lines. In this study, we examine the time- and level-dependent effects of MLL-AF4 conditional expression on cell cycle and differentiation of myelomonocytic leukemia cell line U937. By varying the concentration of tetracycline in growth media, we found that increasing levels of MLL-AF4 expression result in a progressive decrease in growth rate and fraction of S phase cells, paralleled by an increase in percentage of cells expressing CD11b. Our results demonstrate a dosage-dependent effect of MLL-AF4 fusion oncoprotein on cell cycle progression, with increasing expression levels resulting in the accumulation in G1, prolonged doubling time, both findings that might be responsible for the increased resistance to etoposide-mediated cytotoxicity. We propose the cell cycle control exerted by MLL-AF4 may be responsible of resistance to cell-death promoting stimuli in leukemia carrying the t(4;11) translocation.

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Acknowledgements

We are very grateful to Dominique Broccoli for helpful discussion. We thank Gerard Grosveld for U937T cell line, John H Kersey for α-AF4 C15 polyclonal antibodies, Xiangxi Xu and Maureen Murphy for sharing reagents. Supported by Fondazione ‘M. Tettamanti’, Associazione Italiana Ricerca sul Cancro (AIRC) and Ministero Istruzione Università e Ricerca (MIUR).

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Author notes

  1. C Caslini

    Present address: Department of Medical Oncology, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA

  2. A Serna

    Present address: Department of Immunology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA

  3. C Caslini and A Serna: The first two authors equally contributed to this work

Authors and Affiliations

  1. Centro Ricerche M Tettamanti, Clinica Pediatrica Università Milano–Bicocca, Monza, Italy

    C Caslini, A Serna, V Rossi & A Biondi

  2. Divisione di Ematologia, Laboratorio di Terapia Cellulare G Lanzani, Ospedali Riuniti di Bergamo, Italy

    M Introna

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Caslini, C., Serna, A., Rossi, V. et al. Modulation of cell cycle by graded expression of MLL-AF4 fusion oncoprotein. Leukemia 18, 1064–1071 (2004). https://doi.org/10.1038/sj.leu.2403321

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