RCSD1–ABL1-positive acute lymphoblastic leukemia (ALL) is included in Philadelphia chromosome-like (Ph-like) ALL. We have experienced a case of RCSD1–ABL1-positive ALL which was resistant to dasatinib which is a tyrosine kinase inhibitor (TKI) although previous study showed RCSD1–ABL1-positive ALL is sensitive to dasatinib. The aim of this study is to examine the varieties of sensitivity to TKIs in RCSD1–ABL1-positive ALL. Ba/F3 cells were transduced with retroviral vectors expressing fusion of RCSD1 exon 3/ABL1 exon 4 (R3A4; 3042 bp). Leukemogenicity was examined in vitro and in vivo. Phosphorylation antibody array and Western blotting assay were performed in R3A4-Ba/F3 to examine the kinase-activating pathways. Sensitivities to TKIs of R3A4-Ba/F3 were also examined. R3A4-Ba/F3 showed leukemogenicity both in vitro and in vivo.Phosphorylation antibody array showed Tyk2 activation in R3A4-Ba/F3. Western blotting showed that the leukemogenicity of R3A4 involves the Tyk2-STAT2 pathway. R3A4-Ba/F3 was resistant to imatinib and dasatinib but sensitive to pan-JAK family, including Tyk2 inhibitor. Previous opened R3A4 fusion whose fusion point is different from ours was reported to activate STAT5, which was inhibited by dasatinib. Taken together, these findings suggest that the kinase-activating pathways and sensitivities to TKIs vary between fusion sites of RCSD1–ABL1 in Ph-like
