ABSTRACT
ETO2 is a nuclear co-repressor, which plays a critical role in the regulation of the cell cycle, self-renewal capacity, and differentiation of hematopoietic progenitor cells. We identified novel fusion transcripts involving ETO2 and CTCF by RNA-seq in a multiple relapsed AML case. The CTCF-ETO2 and ETO2-CTCF chimeric genes were validated by RT-PCR and Sanger sequencing. In addition, both transcripts apparently promoted cell proliferation via JAK/STAT3 pathway that is sensitive to STAT3 inhibitors. The novel fusions may have prognostic value and pathogenic mechanisms in acute myeloid leukemia.
Subject(s)
Leukemia, Myeloid, Acute , Cell Differentiation/genetics , Cell Proliferation , Hematopoietic Stem Cells/pathology , Humans , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/pathologyABSTRACT
CD19-redirected CAR-T immunotherapy has emerged as a promising strategy for treatment of B cell lymphoma, however, many patients often relapsed due to antigen loss. Therefore, it is urgently needed to explore other suitable antigens targeted by CAR-T cells to cure B cell lymphoma. Igß is a component of the B cell receptor (BCR) complex, which is highly expressed on the surface of lymphoma cells. In this study, we engineered T cells to express anti-Igß CAR with CD28 costimulatory signaling moiety and observed that Igß-CAR T cells could efficiently recognize and eliminate Igß+ lymphoma cells both in vitro and in two different lymphoma xenograft models. The specificity of Igß-CAR T cells was further confirmed through wild type or mutated Igß gene transduction together with Igß-specific knockout in target cells. Of note, both the in vitro and in vivo effect of Igß CAR-T cells was comparable with that of CD19 CAR-T cells. Importantly, Igß CAR-T cells recognized and eradicated patient-derived lymphoma cells in the autologous setting. Lastly, the safety of anti-Igß CAR-T cells could be further enhanced by introduction of the inducible caspase-9 suicide gene system. Collectively, Igß-specific CAR-T cells may be a promising immunotherapeutic approach for B cell lymphoma.