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Acute Lymphoblastic Leukemia

Silencing of the tumor suppressor gene FHIT is highly characteristic for MLL gene rearranged infant acute lymphoblastic leukemia

Leukemia volume 20, pages 264–271 (2006)Cite this article

Abstract

MLL rearranged acute lymphoblastic leukemia (MLL) is an aggressive type of acute lymphoblastic leukemia (ALL), diagnosed predominantly in infants (<1 years of age). Since current chemotherapy fails in >50% of patients with MLL, new therapeutic strategies are desperately needed. For this, understanding the biological features characterizing MLL is necessary. Analysis of gene expression profiles revealed that the expression of the tumor suppressor gene FHIT is reduced in children with MLL rearranged ALL as compared to ALL patients carrying germ line MLL. This finding was confirmed by quantitative real-time PCR. In 100% of the infant MLL cases tested, methylation of the FHIT 5′CpG region was observed, resulting in strongly reduced mRNA and protein expression. In contrast, FHIT methylation in infant and non-infant ALL patients carrying germ line MLL was found in only ∼60% (P⩽0.004). FHIT expression was restored upon exposing leukemic cells to the demethylating agent decitabine, which induced apoptosis. Likewise and more specifically, leukemic cell death was induced by transfecting MLL rearranged leukemic cells with expression vectors encoding wild-type FHIT, confirming tumor suppressor activity of this gene. These observations imply that suppression of FHIT may be required for the development of MLL, and provide new insights into leukemogenesis and therapeutic possibilities for MLL.

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Acknowledgements

We wish to express our gratitude to the members and participating hospitals of the INTERFANT-99 for supporting this study by providing leukemic samples. Members of INTERFANT-99 are: Campbell M (PINDA), Felice M (Argentina), Ferster A (CLCG), Hann I and Vora A (UKCCSG), Hovi L (NOPHO), Janka-Schaub G (COALL), Li CK (Hong Kong), Mann G (BFM-A), Mechinaud F (FRALLE), Pieters R (DCOG), de Rossi G and Biondi A (AIEOP), Rubnitz J (SJCRH), Schrappe M (BFM-G), Silverman L (DFCI), Stary J (CPH), Suppiah R (ANZCHOG), Szczepanski T (PPLLSG), Valscecchi M and de Lorzenzo P (CORS).

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Authors and Affiliations

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

    R W Stam, M L den Boer, M M C J Passier & R Pieters

  2. COALL study group, Hamburg, Germany

    G E Janka-Schaub

  3. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston Massachusetts, Harvard Medical School, Boston, MA, USA

    S E Sallan & S A Armstrong

  4. Division of Pediatric Hematology/Oncology, Children's Hospital, Boston, MA, USA

    S E Sallan & S A Armstrong

  5. INTERFANT-99 Collaborative Study Group,

    R Pieters

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  1. R W Stam
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Correspondence to M L den Boer.

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Financial support: This study was supported by a grant from the Sophia Foundation for Medical Research (SSWO Grant 296)

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Stam, R., den Boer, M., Passier, M. et al. Silencing of the tumor suppressor gene FHIT is highly characteristic for MLL gene rearranged infant acute lymphoblastic leukemia. Leukemia 20, 264–271 (2006). https://doi.org/10.1038/sj.leu.2404074

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