Multiple myeloma (MM) is an incurable haematological malignancy. It is
characterized clinically by an asymptomatic precursor stage, known as monoclonal
gammopathy of undetermined significance (MGUS), which will transform into
symptomatic MM at a rate of 1% per year. Gene promoter hypermethylation by
catalytic conversion of cytosine into 5?methylcytosine at promoter?associated CpG
island is an alternative mechanism of gene inactivation. MicroRNA (miRNA) is a class of
short, single?stranded, non?coding RNA molecules, which will repress the expression of
target protein by sequence?specific binding to the three prime untranslated region of
the corresponding messenger RNA. In carcinogenesis, miRNA can be either oncogenic
when tumour suppressor genes are targeted, or tumour suppressive when oncogenes
are targeted. Despite reports of hypermethylation of multiple protein?coding tumour
suppressor genes, little is known about DNA methylation of non?coding tumour
suppressor miRNA genes in MM.
This thesis aimed to investigate the role of promoter hypermethylation of tumour
suppressor miRNA genes in MM using a candidate miRNA approach. Moreover, the
prognostic significance of tumour suppressor miRNA hypermethylation was studied in
a uniformly?treated cohort of MM patients.
The role of DNA methylation at the promoter of miR?203, miR?34a, miR?34b/c,
miR?124?1, miR?129?2 and miR?224 were studied in MM. The tumour suppressor role
of miR?34b/c, miR?124?1, miR?203 and miR?224 were demonstrated in human
myeloma cell lines (HMCLs). In particular, restoration of miR?203 in MM cells was
shown to inhibit cellular proliferation via targeting and hence direct downregulation of
a proto?oncogene, cyclic AMP responsive element binding protein. There are several
observations in primary MM samples. First, there was frequent methylation of
miR?129?2, miR?203 and miR?224 but infrequent methylation of miR?34a, miR?34b/c
and miR?124?1 in MM at diagnosis. Second, tumour?specific hypermethylation of each
of the miR?203 and miR?224 promoters was detected at comparable frequencies in
MGUS, diagnostic and relapsed/progressed MM, and hence implicated as an early
event in myelomagenesis. Thirdly, miR?129?2 methylation was more frequent in
diagnostic MM than MGUS, and hence implicated in MGUS progression to MM. On the
other hand, despite rare miR?34b/c methylation at diagnosis, miR?34b/c methylation
was frequent at relapse/progression, thereby implicating miR?34b/c methylation in
MM relapse/progression. Fourthly, despite frequent miR?124?1 methylation in HMCLs,
miR?124?1 methylation was rare in both diagnostic and relapsed MM marrow samples,
suggesting that miR?124?1 methylation was acquired during in vitro cell culture.
Finally, the prognostic significance of methylation of a panel of tumour
suppressor miRNAs was studied in a uniformly?treated cohort of MM patients, which
revealed that miR?224 hypermethylation as an independent favourable prognostic
factor for survival.
In conclusion, hypermethylation of tumour suppressor miRNAs is implicated in
the pathogenesis (miR?203, miR?129?2, miR?224), progression (miR?34b/c), and
prognostification (miR?224) of MM. / published_or_final_version / Medicine / Doctoral / Doctor of Philosophy
| Identifer | oai:union.ndltd.org:HKU/oai:hub.hku.hk:10722/174390 |
| Date | January 2011 |
| Creators | Wong, Kwan-yeung., 黃君揚. |
| Contributors | Chim, JCS, Jin, D, Liang, RHS |
| Publisher | The University of Hong Kong (Pokfulam, Hong Kong) |
| Source Sets | Hong Kong University Theses |
| Language | English |
| Detected Language | English |
| Type | PG_Thesis |
| Source | http://hub.hku.hk/bib/B47331513 |
| Rights | The author retains all proprietary rights, (such as patent rights) and the right to use in future works., Creative Commons: Attribution 3.0 Hong Kong License |
| Relation | HKU Theses Online (HKUTO) |
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