Abstract
Mutations in ASXL1 and SETBP1 genes have been frequently detected and often coexist in myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML). We previously showed that coexpression of mutant ASXL1 and SETBP1 in hematopoietic progenitor cells induced downregulation of TGFβ pathway genes and promoted the development of MDS/AML in a mouse model of bone marrow transplantation. However, whether the repression of TGFβ pathway in fact contributes to leukaemogenesis remains unclear. Moreover, mechanisms for the repression of TGFβ pathway genes in ASXL1/SETBP1-mutated MDS/AML cells have not been fully understood. In this study, we showed that expression of a constitutively active TGFβ type I receptor (ALK5-TD) inhibited leukaemic proliferation of MDS/AML cells expressing mutant ASXL1/SETBP1. We also found aberrantly reduced acetylation of several lysine residues on histone H3 and H4 around the promoter regions of multiple TGFβ pathway genes. The histone deacetylase (HDAC) inhibitor vorinostat reversed histone acetylation at these promoter regions, and induced transcriptional derepression of the TGFβ pathway genes. Furthermore, vorinostat showed robust growth-inhibitory effect in cells expressing mutant ASXL1, whereas it showed only a marginal effect in normal bone marrow cells. These data indicate that HDAC inhibitors will be promising therapeutic drugs for MDS and AML with ASXL1 and SETBP1 mutations.
Highlights
Mutations in additional sex combs like 1 (ASXL1) and SET binding protein 1 (SETBP1) genes have been frequently detected and often coexist in myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML)
We previously reported that forced expression of a C-terminally truncated ASXL1 mutant in hematopoietic progenitor cells induced MDS-like diseases, and SETBP1 mutations drove leukaemic transformation in ASXL1-mutated MDS in mouse models[18,19]
We first assessed the role of TGFβ pathway in leukaemogenesis using murine bone marrow cells transformed by a C-terminally truncated form of ASXL1 mutant [ASXL1-MT cells: cells expressing ASXL1 mutation (ASXL1-MT)]18 or those transformed by combined expression of SETBP1-D868N and ASXL1-MT19
Summary
Mutations in ASXL1 and SETBP1 genes have been frequently detected and often coexist in myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML). We previously showed that coexpression of mutant ASXL1 and SETBP1 in hematopoietic progenitor cells induced downregulation of TGFβ pathway genes and promoted the development of MDS/AML in a mouse model of bone marrow transplantation. Vorinostat showed robust growth-inhibitory effect in cells expressing mutant ASXL1, whereas it showed only a marginal effect in normal bone marrow cells These data indicate that HDAC inhibitors will be promising therapeutic drugs for MDS and AML with ASXL1 and SETBP1 mutations. We previously reported that forced expression of a C-terminally truncated ASXL1 mutant in hematopoietic progenitor cells induced MDS-like diseases, and SETBP1 mutations drove leukaemic transformation in ASXL1-mutated MDS in mouse models[18,19]. Mechanisms for the repression of TGFβ pathway genes in ASXL1/ SETBP1-mutated MDS/AML cells have not been fully understood. The repression of TGFβ pathway genes are associated with histone deacetylation at their promoter regions, which can be reversed by treatment with the histone deacetylase (HDAC) inhibitor vorinostat
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