Interaction between Activated JAK-STAT Signaling and Epigenetic Alterations---Biological and Clinical Implications in Human Myeloproliferative Neoplasms

Project: National Science and Technology CouncilNational Science and Technology Council Academic Grants

Project Details

Abstract

Myeloproliferative neoplasms (MPNs) are stem cell-derived clonal disorders. In 2008, the committee members organized by World Health Organization (WHO), 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. Identification of frame-shift mutations clustered in the exon 9 of Calreticulin (CALR) gene in a large proportion of JAK2-unmutated MPN samples in 2013 marks another important milestone in our understanding of MPN, yet the exact molecular pathogenesis of these diseases are still poorly understood. High mobility group A2 (HMGA2), a non-histone DNA binding protein whose 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. Up-regulation of HMGA2 with truncated 3’UTR in transgenic mice could also recapture many phenotypes of MPN. Nevertheless, the clinical significance of HMGA2 as well as its interacting relationship with JAK2 signaling in MPN has never been reported in the past. Our preliminary data showed that some of our MPN patients had increased HMGA2 transcripts. Aberrant HMGA2 upregulation, commonly associated with JAK2V617F mutation and unique clinical phenotypes, inversely correlated with the expression level of let-7 miRNA. JAK2V617F-transfected cells exhibit significantly decreased degree of promoter methylation of HMGA2 as well as LIN28A, an important regulator in let-7 miRNA maturation. We believe the LIN28-let-7-HMGA2 axis is rather critical in the pathogenesis of JAK2-mutated MPNs and might play some roles in the development of CALR-mutated MPNs. Therefore, we put forward this proposal with the following aims: 1) To unveil the nature and functional importance of aberrant HMGA2 expression in MPN cells; 2) To elucidate the molecular mechanisms leading to HMGA2 up-regulation and to identify its downstream pathways in MPNs; 3) To clarify any regulatory interaction and potential synergism between JAK2V617F-activatedd pathway and HMGA2 activity in the pathogenesis of JAK2-mutated MPNs; 4) To investigate possible reciprocal interactivity between CALR mutation and aberrant HMGA2 expression in the pathogenesis of CALR-mutated (JAK2-unmutated) MPNs. The results shall help unearth the critical roles of LIN28-let-7-HMGA2 signaling axis and its potential coordination with either JAK2 or CALR mutation in the initiation and propagation of MPN. The unique molecular mechanisms identified here might further facilitate the re-categorization of a distinctive subgroup of MPN patients, and could eventually lead to rationally designed targeted therapies aiming at eradicating these cumbersome diseases.

Project IDs

Project ID:PC10401-0627
External Project ID:MOST103-2314-B182-051-MY3
StatusFinished
Effective start/end date01/08/1531/07/16

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