Epigenetic Alteration and miRNA Regulation in the Pathogenesis of Human Myeloproliferative Neoplasms

Myeloproliferative neoplasms (MPN) are a stem cell-derived clonal disorders of hematopoietic system. In 2008, the committee members organized by World Health Organization (WHO) for the purpose of classification of myeloid neoplasms, citing the high resemblance of clinical characteristics as well as strong affiliation with JAK2V617F mutation, designated polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) into the subcategory of classical MPN. However, it remains unclear why the same acquired mutation in the JAK2 gene cause three clinical entities that are more or less distinct. And despite mutations in a number of genes, including MPL, LNK, CBL, IDH1, IDH2, TET2, EZH2, DNMT3A, ASXL1, SF3B1, IKZF1, TP53, CUX1, and others have been identified in a relatively short span of time, the molecular mechanisms for the pathogenesis of these diseases are still not fully understood. HMGA2, a non-histone DNA binding protein of which the mRNA could be regulated by let-7 microRNA, is known to promote transcription of genes important in cell proliferation, survival and cell cycle progression. Its over-expression has been found in a variety of human cancers. In a recent study, up-regulation of HMGA2 with truncated 3’UTR in transgenic mouse recaptures many phenotypes of MPN. Nevertheless, the true incidence of HMGA2 overexpression in clinical MPN samples has never been reported in the past. Moreover, how HMGA2 is regulated and what’s its functional importance in the pathogenesis of MPN remain to be elucidated. Our preliminary data demonstrated that about one-fourth of some 38 MPN patients screened had increased HMGA2 transcripts level in their granulocytes. This proposal firstly aims to delineate the accurate incidence and prognostic impacts of aberrant HMGA2 expression in a larger cohort of MPN patients. We will then proceed with the following specific aims: 1) To unveil the functional importance of HMGA2 and its downstream effector pathways in the pathogenesis of MPN; 2) to identify the molecular mechanisms leading to aberrant HMGA2 expression in MPN (including chromosome abnormality, post-transcriptional regulation by let-7 miRNA, the expression of LIN28, states of inflammation, and other epigenetic mutations); 3) To investigate the coordinated synergism among let-7-HMGA2 axis, JAK2V617F mutation, and inflammatory cytokine pathways in the development of MPN. The results shall help elucidate the critical roles of interactive let-7-HMGA2 signaling and its potential coordination with JAK2 mutation as well as cytokines in the pathogenesis of MPN. The findings might not be applicable to all patients considering MPN being a heterogeneous disease, but the unique molecular mechanisms and signal transduction activities identified here might further help re-categorize a distinctive subgroup of MPN patients as well as lead to rationally designed targeted therapies aiming at eradicating this cumbersome disease.

Project ID:PC10207-0442
External Project ID:NSC102-2314-B182-047