title: Epigenetic dysregulation of leukaemic HOX code in MLL-rearranged leukaemia mouse model.
abstract: HOX genes are frequently dysregulated in human leukaemia with the gene rearrangement between mixed lineage leukaemia (MLL) and partner genes. The resultant MLL fusion proteins are known to mediate leukaemia through disruption of the normal epigenetic regulation at the target gene loci. To elucidate the pathogenic role of MLL fusion proteins in HOX dysregulation in leukaemia, we generated a novel haematopoietic lineage-specific Mll-Een knock-in mouse model using a Cre-mediated inversion strategy. The Mll(Een) (/+) invertor mice developed acute myeloid leukaemia, with organomegaly of the spleen, liver and mesenteric lymph nodes caused by infiltration of blast cells. Using Mll-Een-expressing leukaemic cell lines derived from bone marrow of Mll(Een) (/+) mutant mice, we showed that induction of Hox genes in leukaemic cells was associated with hypomethylated promoter regions and an aberrant active chromatin state at the Hox loci. Knock-down of Prmt1 was insufficient to reverse the active chromatin status and the hypomethylated Hox loci, suggesting that Prmt1-mediated histone arginine methylation was only partially involved in the maintenance of Hox expression in leukaemic cells. Furthermore, in vivo analysis of bone marrow cells of Mll(Een) (/+) mice revealed a Hox expression profile similar to that of wild-type haematopoietic stem cells. The leukaemic Hox profile was highly correlated with aberrant hypomethylation of Hox promoters in the mutant mice, which highlights the importance of DNA methylation in leukaemogenic mechanisms induced by MLL fusion proteins. Our results point to the involvement of dynamic epigenetic regulations in the maintenance of the stem cell-like HOX code that initiates leukaemic stem cells in MLL-rearranged leukaemia. This provides insights for the development of alternative strategies for leukaemia treatment.
authors.affiliation: SH Ho Foundation Research Laboratories, Department of Pathology, Hong Kong Jockey Club Clinical Research Centre, University of Hong Kong, Pokfulam, Hong Kong, SAR, China; Centre for Reproduction, Development and Growth, Li Ka Shing Faculty of Medicine, University of Hong Kong, Pokfulam, Hong Kong, SAR, China.
authors.forename: Ray Kit
authors.initials: RK
authors.lastname: Ng
authors.forename: Cheuk Ting
authors.initials: CT
authors.lastname: Kong
authors.forename: Chi Chiu
authors.initials: CC
authors.lastname: So
authors.forename: Wing Chi
authors.initials: WC
authors.lastname: Lui
authors.forename: Yuen Fan
authors.initials: YF
authors.lastname: Chan
authors.forename: Ka Chun
authors.initials: KC
authors.lastname: Leung
authors.forename: Kam Chung
authors.initials: KC
authors.lastname: So
authors.forename: Ho Man
authors.initials: HM
authors.lastname: Tsang
authors.forename: Li Chong
authors.initials: LC
authors.lastname: Chan
authors.forename: Mai Har
authors.initials: MH
authors.lastname: Sham
mesh_terms: D000818:Animals; D002678:Chimera; D019175:DNA Methylation; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic; D005260:Female; D055785:Gene Knockdown Techniques; D015321:Gene Rearrangement; D005801:Genes, Homeobox / Q000235:genetics*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D007951:Leukemia, Myeloid / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics*; D050596:Oncogene Fusion; D010641:Phenotype; D011401:Promoter Regions, Genetic
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C105159:SH3GL1 protein, human; D051788:Myeloid-Lymphoid Leukemia Protein
keywords: DNA methylation; HOX; MLL-EEN; epigenetics; leukaemia