Epigenetic dysregulation of ZEB1 is involved in LMO2-promoted T-cell acute lymphoblastic leukaemia leukaemogenesis

Biochimica Et Biophysica Acta. Molecular Basis of Disease
Chao WuShuang Yang

Abstract

T-cell acute lymphoblastic leukaemia (T-ALL) is a hematological malignancy caused by the accumulation of genomic lesions that affect the development of T-cells. ZEB1, a member of zinc finger-homeodomain family transcription factor, exhibits crucial function in promoting T-cell differentiation and potentially acts as a tumor suppressor in T-ALL. However, the molecular mechanism by which ZEB1 regulates T-ALL leukaemogenesis remains obscure. Here, we showed that oncogenic LIM only 2 (LMO2) could recruit Sap18 and HDAC1 to assemble an epigenetic regulatory complex, thus inducing histone deacetylation in ZEB1 promoter and chromatin remodeling to achieve transcriptional repression. Furthermore, downregulation of ZEB1 by LMO2 complex results in an increased leukaemia stem cell (LSC) phenotype as well as unsensitivity in response to methotrexate (MTX) chemotherapy in T-ALL cells. Importantly, we demonstrated that Trichostatin A (TSA, a HDAC inhibitor) addition significantly attenuates MTX unsensitivity caused by dysfunction of LMO2/ZEB1 signaling. In conclusion, these findings have identified a molecular mechanism underlying LMO2/ZEB1-mediated leukaemogenesis, paving a way for treating T-ALL with a new strategy of epigenetic inhibitors.

Citations

Mar 28, 2020·International Journal of Molecular Sciences·Geoffrey BrownIsidro Sánchez-García

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