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Acute Leukemias

The key role of stem cell factor/KIT signaling in the proliferation of blast cells from Down syndrome-related leukemia

Leukemia volume 23, pages 95–103 (2009)Cite this article

Abstract

Transient leukemia (TL) has been observed in approximately 10% of newborn infants with Down syndrome (DS). Although treatment with cytarabine is effective in high-risk TL cases, approximately 20% of severe patients still suffer early death. In this study, we demonstrate abundant KIT expression in all 13 patients with GATA1 mutations, although no significant difference in expression levels was observed between TL and acute myeloid leukemia. Stem cell factor (SCF) stimulated the proliferation of the TL cells from five patients and treatment with the tyrosine kinase inhibitor imatinib suppressed the proliferation effectively in vitro. To investigate the signal cascade, we established the first SCF-dependent, DS-related acute megakaryoblastic leukemia cell line, KPAM1. Withdrawal of SCF or treatment with imatinib induced apoptosis of KPAM1 cells. SCF activated the RAS/MAPK and PI3K/AKT pathways, followed by downregulation of the pro-apoptotic factor BIM and upregulation of the anti-apoptotic factor MCL1. Although we found novel missense mutations of KIT in 2 of 14 TL patients, neither mutation led to KIT activation and neither reduced the cytotoxic effects of imatinib. These results suggest the essential role of SCF/KIT signaling in the proliferation of DS-related leukemia and the possibility of therapeutic benefits of imatinib for TL patients.

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Acknowledgements

We thank Dr K Kageyama (Hirosaki University Graduate School of Medicine) for helpful discussion. We are grateful to Dr K Kawakami, S Morinaga, M Migita, K Kato, H Kanegane, M Miura, T Nakano, T Taga, A Shimada, D Hasegawa for clinical samples. XG is supported by a fellowship from the Ministry of Education, Science, Sports and Culture. This work was supported by Grants-in-Aid for Scientific Research and Grants-in-Aid for Scientific Research on Priority Areas from the Ministry of Education, Science, Sports and Culture, and Grants from Ministry of Health Labour and Welfare.

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Authors and Affiliations

  1. Department of Pediatrics, Hirosaki University Graduate School of Medicine, Hirosaki, Japan

    T Toki, R Kanezaki, G Xu, T Sato, K Suzuki & E Ito

  2. Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto, Japan

    S Adachi & H Fujino

  3. Department of Pediatrics, Ehime University Graduate School of Medicine, Toon, Japan

    H Tauchi

  4. Department of Pediatrics, Iwate Medical University, Morioka, Japan

    M Endo

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  1. T Toki
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Correspondence to E Ito.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Toki, T., Kanezaki, R., Adachi, S. et al. The key role of stem cell factor/KIT signaling in the proliferation of blast cells from Down syndrome-related leukemia. Leukemia 23, 95–103 (2009). https://doi.org/10.1038/leu.2008.267

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