Functional analysis of novel chimeric gene SNX2-ABL1 detected in childhood acute lymphoblastic leukemia

2014 Fiscal Year Final Research Report

• Project/Area Number: 25860899
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Pediatrics
• Research Institution: Tokyo University of Science
• Principal Investigator: IIJIMA Kazutoshi 東京理科大学, 工学部, 助教 (30468508)
• Research Collaborator: TOMITA Osamu 順天堂大学, 医学部, 助教 ; SUZUKI Ryo 東京理科大学大学院, 総合化学研究科 ; OCHI Kentaro 東京理科大学, 工学部 ; KOMARU Kanae 東京理科大学, 工学部
• Project Period (FY): 2013-04-01 – 2015-03-31
• Keywords: 白血病 / シグナル伝達 / チロシンキナーゼ阻害剤

Outline of Final Research Achievements

Therapeutic application of tyrosine kinase inhibitors (TKIs) has significantly improved the outcome of BCR-ABL1-positive B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Recently, novel ABL1-related chimeric transcripts were identified. In this study, we investigated the functional characteristics of SNX2-ABL1 protein. IL-3-independent proliferative ability was acquired by induction of SNX2-ABL1 as similar as BCR-ABL1 in IL3-dependent mouse pro-B Ba/F3 cells. SNX2-ABL1-expressing Ba/F3 cells showed rather lower sensitivity against TKIs, especially dasatinib. Then, the mechanism of resistance to dasatinib was investigated. As a result, SNX2-ABL1-expressing Ba/F3 cells showed different phosphorylation pattern of those of BCR-ABL1 and the phosphorylation of intracellular proteins, especially CrkL, p44/42 MAPK, STAT5, are only partially inhibited by TKI treatment. From gene expression analysis, high expression of Igf-1 in SNX2-ABL1 expressing cells was observed.

Free Research Field

小児血液学