The key role of stem cell factor/KIT signaling in the proliferation of blast cells from Down syndrome-related leukemia.
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.
Toki
T
T
Department of Pediatrics, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
Kanezaki
R
R
Adachi
S
S
Fujino
H
H
Xu
G
G
Sato
T
T
Suzuki
K
K
Tauchi
H
H
Endo
M
M
Ito
E
E
D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004314:Down Syndrome / Q000150:complications*; D005260:Female; D050982:GATA1 Transcription Factor / Q000235:genetics; D006801:Humans; D000068877:Imatinib Mesylate; D007223:Infant; D007231:Infant, Newborn; D007938:Leukemia / Q000209:etiology / Q000473:pathology*; D008297:Male; D009154:Mutation; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction / Q000502:physiology*; D019089:Stem Cell Factor / Q000032:analysis / Q000235:genetics / Q000502:physiology*
D001549:Benzamides; D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human; D010879:Piperazines; D011743:Pyrimidines; D019089:Stem Cell Factor; D000068877:Imatinib Mesylate