Clinical Significance of Tyrosine Kinase and Molecular Targeted Therapy in Pediatric Hematologic Disorders

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  • 小児造血器疾患におけるチロシンキナーゼの臨床的意義とその阻害剤による治療

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Receptor tyrosine kinases are considered to play an important role for tumorigenesis. Among them, a class III receptor-type tyrosine kinase family, including FMS-like tyrosine kinase 3 (FLT3), stem cell factor receptor (KIT), and platelet-derived growth factor receptor (PDGFR), which is expressed on immature hemalopoiectic stem cells, plays an important role for cell growth, survival, differentiation, and migration. Recently, internal tandem duplication (ITD) and mutations of D835/I836 in the tyrosine kinase (TK) domain of the FLT3 gene have been reported in adult and pediatric acute myeloid leukemia (AML), and myelodysplastic syndrome (MDS), but not in acute lymphoblastic leukemia (ALL). The frequency and clinical significance of mutations of the FLT3, KIT, and PDGFRA genes are herereviewed in pediatric leukemias. Interestingly, FLT3 TK-mutations were found in about 20% of hyperdiploid ALL patients and infant ALL patients with MLL rearrangements. These ALL patients with mutations tended to have a poorer prognosis than those without the mutations. KIT mutations were found in 8 of 46 AML patients with t (8;21) out of 135 AML patients treated on the AML99 protocol. Mutations of PDGFRA gene were found in 2 of 114 AML patients in our study. These results suggested that mutations of the FLT3, KIT and PDGFRA genes may be one of the second hit mutations involved in the development of pediatric leukemia and are associated with specific chromosomal abnormalities. We also review here clinical significance of nucleophosmin and JAK genes which are associated with these tyrosine kinases. Recent progress of molecular targeted therapy against pediatric hematologic disorders wasalso reviewed.

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