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Acute Leukemias

High BRE expression in pediatric MLL-rearranged AML is associated with favorable outcome

Leukemia volume 24, pages 2048–2055 (2010)Cite this article

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Abstract

Translocations involving the mixed lineage leukemia (MLL) gene, localized at 11q23, frequently occur in pediatric acute myeloid leukemia (AML). We recently reported differences in prognosis between the different translocation partners, suggesting differences in biological background. To unravel the latter, we used microarrays to generate gene expression profiles of 245 pediatric AML cases, including 53 MLL-rearranged cases. Thereby, we identified a specific gene expression signature for t(9;11)(p22;q23), and identified BRE (brain and reproductive organ expressed) to be discriminative for t(9;11)(p22;q23) (P<0.001) when compared with other MLL subtypes. Patients with high BRE expression showed a significantly better 3-year relapse-free survival (pRFS) (80±13 vs 30±10%, P=0.02) within MLL-rearranged AML cases. Moreover, multivariate analysis identified high BRE expression as an independent favorable prognostic factor within pediatric AML for RFS (HR=0.2, P=0.04). No significant differences were identified for 3-year event-free survival or for 3-year overall survival. Forced expression of BRE did not result in altered cell proliferation, apoptosis or drug sensitivity, which could explain the favorable outcome. In conclusion, overexpression of the BRE gene is predominantly found in MLL-rearranged AML with t(9;11)(p22;q23). Although further investigation for the role of BRE in leukemogenesis and outcome is warranted, high BRE expression is an independent prognostic factor for pRFS in pediatric AML.

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Acknowledgements

We thank Dr Yiu-Loon Chui, Department of Chemical Pathology and Sir YK Pao Center for Cancer, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, NT, Hong Kong SAR, China, for providing the BRE antibody. Furthermore, we thank Dr E Hulleman for her input in the transfection experiments. This work was funded by the NWO ‘Netherlands Organization for Scientfic Research’ (BVB) and KOCR ‘Kinder-Oncologisch Centrum Rotterdam’ (BVB, IHIM).

Author contributions

BVB designed and performed research and wrote the paper; STJCMP and IHIM performed research. CM and RM performed LDI–PCR to identify the MLL rearrangements. VH, GJK, ESJMB, DR, UC, AB, and JS and JT made this research possible by collecting patient samples and characteristics in their own study groups and providing additional information; MMH-E, CMZ and RP designed and supervised research and wrote the paper.

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Authors and Affiliations

  1. Pediatric Oncology/Hematology, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands

    B V Balgobind, C M Zwaan, T J C M Arentsen-Peters, I H I M Hollink, M L den Boer, R Pieters & M M van den Heuvel-Eibrink

  2. AML-BFM Study Group, Pediatric Oncology/Hematology, Medical School Hannover, Hannover, Germany

    D Reinhardt

  3. Dutch Childhood Oncology Group (DCOG), The Hague, The Netherlands

    V de Haas

  4. Pediatric Oncology/Hematology, VU University Medical Center, Amsterdam, The Netherlands

    G J L Kaspers

  5. Pediatric Oncology/Hematology, Beatrix Children's Hospital, University Medical Center Groningen, Groningen, The Netherlands

    E S J M de Bont

  6. Hematology, St Louis Hospital, Paris, France

    A Baruchel

  7. Pediatric Hematology/Oncology, 2nd Medical School, Charles University, Prague, Czech Republic

    J Stary

  8. Institute of Pharmaceutical Biology, ZAFES, Diagnostic Center of Acute Leukemias (DCAL), Frankfurt, Germany

    C Meyer & R Marschalek

  9. Pediatric Hematology/Oncology, University Hospital Muenster, Muenster, Germany

    U Creutzig

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Correspondence to M M van den Heuvel-Eibrink.

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Balgobind, B., Zwaan, C., Reinhardt, D. et al. High BRE expression in pediatric MLL-rearranged AML is associated with favorable outcome. Leukemia 24, 2048–2055 (2010). https://doi.org/10.1038/leu.2010.211

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