Leukemic cells expressing NCOR1-LYN are sensitive to dasatinib in vivo in a patient-derived xenograft mouse model

Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a distinct subtype of B-ALL with a poor prognosis. Rearrangement of LYN is a recurrent genetic abnormality in Ph-like ALL, but functional analysis of LYN-related fusion genes identified in ALL has not been reported. In this study, we performed functional analysis of the NCOR1-LYN fusion gene identified in a pediatric Ph-like ALL patient to establish its potential for molecular targeted therapy. Retroviral transduction of interleukin (IL)-3-dependent Ba/F3 cells with NCOR1-LYN enabled IL-3-independent proliferation, with constitutive phosphorylation of the tyrosine residues of the LYN kinase domain in the fusion protein. Replacing tyrosine residues with phenylalanine in the LYN kinase domain abolished IL-3 independence. Tyrosine kinase inhibitor dasatinib killed Ba/F3 cells expressing NCOR1-LYN in vitro accompanied by dephosphorylation of the tyrosine residues of the LYN kinase domain in the fusion protein.

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Tomii T, Imamura T, Tanaka K, Kato I, Mayumi A, Soma E, Yano M, Sakamoto K, Mikami T, Morita M, Kiyokawa N, Horibe K, Adachi S, Nakahata T, Takita J, Hosoi H