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:PC10308-0666
External Project ID:MOST103-2314-B182-051-MY3
External Project ID:MOST103-2314-B182-051-MY3
Status | Finished |
---|---|
Effective start/end date | 01/08/14 → 31/07/15 |
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