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  • Original Paper
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MLL-AF9 oncogene expression affects cell growth but not terminal differentiation and is downregulated during monocyte–macrophage maturation in AML-M5 THP-1 cells

Oncogene volume 22, pages 8671–8676 (2003)Cite this article

Abstract

The MLL-AF9 oncogene – one of the most frequent MLL/HRX/ALL-1 rearrangements found in infantile and therapy-related leukaemias – originates from t(9;11)(p22;q23) and is mainly associated with monocytic acute myeloid leukaemia (AML-M5; FAB-classification). Here, we investigated the MLL-AF9 function by means of an antisense phosphorothioate-oligodeoxyribonucleotide (MLL-AF9-PS-ODNas) using the THP-1 AML-M5 cell line carrying t(9;11). Having confirmed that MLL-AF9-PS-ODNas induces strong inhibition of THP-1 cell growth, but only a moderate increase in apoptosis, we found that MLL-AF9-PS-ODNas did not induce morpho-functional terminal differentiation or restore M-CSF-, G-CSF- or GM-CSF-induced differentiation. Moreover, THP-1 cells showed the same phenotype with/without MLL-AF9-PS-ODNas. In THP-1 cells differentiated to mature macrophage-like cells by PMA/TPA or ATRA, MLL-AF9 expression was downregulated. Thus, in the monocytic lineage, MLL-AF9 may be expressed only in early phases and can induce deregulated amplification in both nonmalignant and malignant cells, maintaining the monocytic phenotype without blocking final maturation. Our findings suggest that: (1) as well as directly promoting cell growth, MLL-AF9 may also indirectly determine phenotype; (2) other leukaemogenic mutations associated with MLL-AF9-related leukaemias should be searched for mainly in processes of resistance to apoptosis (where MLL-AF9 may play only a limited role) and differentiation blockage (where MLL-AF9 may play no role).

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Acknowledgements

This work was partially supported by grants from AGEOP (Associazione Genitori Ematologia Oncologia Pediatrica), by Università di Bologna (funds for selected research topics), by MURST/FISR DM 16-10-2000 (Fondo Integrativo Specials per la Ricerca), by MURST ex 60% and by CNR (Progetto strategico oncologia SP6 no. 02.00412.ST97). FF and MF were supported by AGEOP; VM and LM by MURST/FISR. We are grateful to Robin MT Cooke for skilled scientific editing.

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Authors and Affiliations

  1. Department of Paediatrics, University of Bologna, Policlinico S. Orsola Malpighi, Bologna, 40138, Italy

    Andrea Pession, Vincenzo Martino, Roberto Tonelli, Claudia Beltramini, Giulia Biserni, Monica Franzoni, Francesea Freccero, Luca Montemurro & Guido Paolucci

  2. Paediatric Haematology/Oncology, IRCCS Policlinico SanMatteo, University of Pavia, Pavia, Italy

    Franco Locatelli

  3. Institute of Haematology and Medical Oncology ‘L.A. Seragnoli’, University of Bologna, Policlinico S. Orsola Malpighi, Bologna, 40138, Italy

    Laura Pattacini

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  1. Andrea Pession
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  2. Vincenzo Martino
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Correspondence to Andrea Pession.

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Pession, A., Martino, V., Tonelli, R. et al. MLL-AF9 oncogene expression affects cell growth but not terminal differentiation and is downregulated during monocyte–macrophage maturation in AML-M5 THP-1 cells. Oncogene 22, 8671–8676 (2003). https://doi.org/10.1038/sj.onc.1207125

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