Abstract LB-155: Molecular targeted therapy of stem cell leukemia-lymphoma induced by ZNF198-FGFR1

Abstract

Abstract Chimeric ZNF198-FGFR1 tyrosine kinase induces patients developing stem cell leukemia-lymphoma syndrome (SCLL), a novel hematological malignancy characterized by rapid transformation to acute myeloid leukemia and T-lymphoblastic lymphoma. Current therapy is inadequate. Using array comparative genomic hybridization (aCGH) we have previously demonstrated that a loss of TCR is a crucial event that perturbed the final maturation stages of T cell development and induced double positive T-lymphoma formation. However, TCR knockout mice did not show T-cell lymphoma development, which indicates that deletion of TCR is unsufficient to induce T-lymphoblastic lymphoma formation. Here we demonstrate that the constitutive activation of Notch1 is frequently seen in the lymphoma from ZNF198-FGFR1 transduced and transplanted mice, in consistent with high expression of the majority of known downstream targets of Notch1. Using ZNF112 cells, a newly derived cell lines from one disease mouse bone marrow, as a model system we found that both DAPT (a γ-secretase inhibitor to block Notch signaling) and transcriptional knockdown of either Notch1 or its co-activator MAML1 via shRNA in ZNF112 cells can significantly delay or prevent the leukemogenesis in syngeneic transplanted mice. These data demonstrate the importance of Notch signaling in the etiology of this disease and provide an important clinical implication that tyrosine kinase inhibitors plus drugs inhibiting Notch signaling can be a promising strategy to treat SCLL patients. This work was supported by grant CA076167 from the National Institutes of Health. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-155.