Shamshudin, Wati @ Hayati Mohd
(2020)
Influence of tert gene expression, telomerase activity and telomere length in relation to imatinib mesylate resistance in Malaysian chronic myeloid leukaemia patients.
PhD thesis, Universiti Sains Malaysia.
Abstract
Chronic myeloid leukaemia (CML) is a myeloproliferative neoplasm
diagnosed by the presence of the BCR-ABL fusion gene which produces a tyrosine
kinase to signal a proliferation of white blood cells. The introduction of imatinib
mesylate in early 2000, has dramatically increased the survival of affected patients
and changed the disease management. However, failure to completely eradicate
leukaemic cells and the escape of these cells from previous control has led to an
intensive search for the mechanisms of resistance and subsequent treatments by
which to overcome the resistance. Meanwhile, telomerase regulation and telomere
maintenance are the critical factors in cell proliferation and survival which plays
important roles in development of cancers. Considering telomerase as an important
component in cell regulations, it is postulated that telomerase might be one of the
oncogenesis mechanism in CML development and might contribute in the resistance
mechanism of imatinib mesylate. A total of 98 CML patients were recruited from
four collaborated hospitals over the country which are Hospital Pulau Pinang,
Hospital Sultanah Aminah, Hospital Raja Permaisuri Bainun and Pusat Perubatan
Universiti Kebangsaan Malaysia. Samples were also collected from Hospital USM
which is the research center for this study. CML patients treated with imatinib were
enrolled into this study and grouped as good response and resistance according to
response of the imatinib mesylate treatment. Sixty-six of patients with good response
at the beginning of samples collection and 32 patients with resistance response were
managed to recruited. However, only 90 samples were able to proceed with DNA
and RNA extraction while 79 samples were successfully applied for protein
extraction due to poor quality of samples obtained. Range of age was between 71 to
77 years old and represented of main ethnicity in Malaysia which were Malay,
Chinese and Indian. The analysis of hTERT expression level, telomerase activity and
length of telomere were performed. The up regulated of hTERT expression and the
presence of telomerase activity were found up to 90% in CML patients recruited in
this study regardless of response group. This indicated that telomerase regulations as
the indicator of cancer events in CML. However the telomerase regulations might not
directly influenced the response and resistance group of treated patients.
Comparison between good response and resistance group showed no significant
difference (p=0.463 in hTERT expression and and p=0.961 in telomerase activity).
Comparison of telomere length in both groups were also showed no significant
difference (p=0.228). The findings indicated that hTERT expression, telomerase
activity and telomere length may not directly influnced the resistance to imatinib
mesylate treatment. To the best of our knowledge, there is no study comparing the
expression and activity of telomerase in group of difference response to imatinib
treatment in CML patients. This could consider that hTERT and the activitiy of
telomerese together with telomere length in CML might have different contributions
in resistance development compared to other solid tumours. Further more,
investigations with a larger number of samples is warranted to confirm the potential
influence of the telomerase and telomere components in the leukaemogenesis and
imatinib resistance in Malaysian CML patients.
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