GADD45G ACTS AS A NOVEL TUMOR SUPPRESSOR IN AML

Abstract

State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China (People's Republic) Acute myeloid leukaemia (AML) is an aggressive hematologic neoplasm with distinct molecular and genetic features which is characterized by differentiation blockade and uncontrolled proliferation of malignant clones of immature myeloid cells. The growth arrest and DNA-damage induced 45 (GADD45) family protein GADD45g, has been shown to mediate DNA repair, cell cycle, senescence and apoptosis in response to various physiological and environmental stressors. Altered expression of GADD45g has been observed in multiple types of solid tumors, the function of GADD45g in hematopoietic malignancies remains almost completely unknown. Here, we found that GADD45g expression was preferentially silenced in AML, especially in AML with MLL rearrangements and FLT3-ITD mutations, and reduced expression of GADD45g correlates with poor prognosis in AML patients. Ectopic expression of GADD45g suppresses leukemic growth, induced apoptosis, senescence and differentiation of AML cells in vitro and in vivo. What's more, GADD45g caused downregulation of DNA repair proteins, resulting in inhibition of DNA double-strand break repair pathways and leading to DNA damage accumulation in AML cells. Moreover, GADD45g is epigenetically silenced in AML by both promoter DNA methylation and histone deacetylation, while the HDACi is more powerful. Exogenous expression of FLT3-ITD and MLL-AF9 repress GADD45G expression in AML, and the expression of GADD45G could be significantly induced by the small-molecule inhibitors FLT3 TKI or BRD4i target FLT3 or MLL respectively. Furthermore, the combination of HDACi and FLT3 TKI or BRD4i exerted a synergistic effect against FLT3-ITD+ or MLL-rearranged AML, respectively. These findings suggest that GADD45G may act as a tumor suppressor in AML and provide a novel and promising therapeutic target for AML.