Children with Down syndrome (DS) are predisposed to developing leukemia. A leukemoid reaction occurring uniquely in approximately 10% of newborn infants with DS referred to as transient leukemia (TL). This disorder, in most cases, resolves spontaneously within three months after birth. Of all TL patients approximately 20–30% develop myeloid leukemia (ML-DS) within four years. Although treatment with low dose cytarabine is effective in high-risk TL cases, about 20% of severe patients still suffer early death. Improved treatments for TL are necessary for a better long-term prognosis of DS patients. In this study, we demonstrate abundant KIT expression in all 13 TL patients examined, although no significant difference in expression levels was observed between TL and acute myeloid leukemia (AML). Stem cell factor (SCF) mRNA was expressed at extremely low levels in TL cells and there were no significant differences in SCF expression between TL and AML. SCF stimulated the proliferation of the TL cells from all five patients examined and treatment with the tyrosine kinase inhibitor imatinib suppressed the proliferation and KIT phosphorylation effectively in vitro. To investigate the signal cascade, we established the first SCF-dependent, ML-DS 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 two of 14 TL patients, functional analysis using KPAM1 cells showed that 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 KIT-targeting tyrosine kinase inhibitors for TL patients.

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