Expression of survival and apoptotic molecules in response to early stage chemotherapy in acute myeloid leukaemia
Acute myeloid leukaemia (AML) is a haematological malignancy characterised by a predominance of myeloid precursor cells that leads to death if not treated. A major factor in the failure of AML chemotherapy is due to the acquisition of multidrug resistance (MDR) by the malignant myeloblast. Factor...
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| Format: | Thesis |
| Language: | English |
| Published: |
2013
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| Subjects: | |
| Online Access: | http://psasir.upm.edu.my/id/eprint/103828/1/STEPHNIE%20YIAU%20KANG%20XIAN%20-%20IR.pdf |
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| Summary: | Acute myeloid leukaemia (AML) is a haematological malignancy characterised by a
predominance of myeloid precursor cells that leads to death if not treated. A major
factor in the failure of AML chemotherapy is due to the acquisition of multidrug
resistance (MDR) by the malignant myeloblast. Factors such as cytokines, activation
of signalling pathway mediators and Bcl-2 family proteins contributes to cell survival,
thus leading to MDR. Bone marrow aspirate was collected a month after induction
therapy to determine complete remission (CR). It is postulated that the treatment
outcome could be determined during early induction therapy through the expression
pattern of cellular molecules in peripheral blood. The expression patterns of stem cell
marker, CD34, c-Kit receptor (CD117), cytokines and their receptors, signalling
mediators of the PI3K/Akt and MAP kinase pathway, and Bcl-2 family proteins were
observed in the peripheral blood of AML patients collected before and/or during Day
3 of induction therapy with anthracycline and cytarabine arabinoside (Ara-C).
Expression were measured using flow cytometry for the percentage of cells expressing and geometric mean fluorescent intensity (MFI), as well asRT-PCR. Results showed that the percentage of cells expressing IL-1β (p=0.028), the MFI of IL-18Rα (p=0.01), MFI ( p=0.007) and mRNA levels (p=0.038) of TNF-α, MFI of DR5 (p=0.02) and
MFI of pAkt-T308 (p=0.038) was found to be significantly higher in samples of
sensitive patients prior to induction therapy. Untreated resistant samples were found
to have significantly higher MFI for pFKHR (p=0.05). During induction therapy, we
found that in sensitive samples,IL-18Rα was found to be significantly higher in the
percentage of expressing cells (p=0.014) and the MFI (p=0.02)was higher as well.
These treated sensitive samples were also found to have significantly higher pp38 MFI (p=0.039). Treated resistant samples were found to have significantly higher
percentage of CD34 (p=0.028) and pBAD (p=0.014) expressing cells. Spearman
Rank-order correlation analysis showed that there is no correlation between the MFI
and the mRNA transcript of cytokine and its receptors. Similar correlations analysis were also observed between cytokines and receptors with signalling mediators and
apoptotic molecules, pBAD and Bim. Some of these correlations corresponded to the
cytokines role in apoptosis and survival but there are some contradictions. Molecules
such as DR5, CD34, pFKHR and pBAD are potential prognostic markers of treatment
outcome but some might not be suitable markers of treatment outcome at the early
stages of induction therapy. |
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