Indicators of apoptosis and proliferation in haematological malignancies : with special reference to drug resistance and prognosis

Successful treatment of acute myeloid leukaemia (AML) and high-grade non-Hodgkin's lymphoma (HG- NHL) is hampered by development of drug resistance. A better understanding of mechanisms responsible for drug resistance and the identification of factors that predict response to therapy is essential to improve treatment. Alterations in balance of proliferation/apoptosis and/or alterations in expression of apoptosis-regulatory proteins (ARP) e.g. p53 and BCL-2 family, can contribute to drug resistance and tumourigenesis. The aim of this thesis was to investigate the role of apoptosis, expression of ARP and aspects of proliferation in drug resistance in AML and as potential predictive factors in HGNHL.

We observed a balance between apoptosis and proliferation in leukaemic drug-resistant cell lines, which suggest that the elimination of drug-sensitive fractions together with re-growth of drug-resistant clones result in development of drug resistance. Studies on the influence of the cytostatic drug daunorubicin (DNR) on apoptosis-induction in AML blast cells, showed that induction of apoptosis was dependant on DNR accumulation and that intraclonal heterogeneity in intracellular drug accumulation and subsequently apoptosis might allow for selection of inherently drug-resistant AML clones, thus contributing to relapse in AML patients.

A variable clinical outcome is observed in diffuse large B-cell lymphomas (DLBL). This lymphoma group has the potential to be further sub-grouped according to underlying molecular features. Our studies on apoptosis, proliferation and expression of selected APR in HG-NHL showed that DLBL could not be subdivided according to such parameters. The International Prognostic Index (IPI) for HG-NHL based on clinical parameters, however the ability to effectively individualise therapy for patients depends on the identification of underlying biological factors to complement the IPI. The investigation of apoptosis, proliferation and the expression of ARP in HG-NHL as potential predictive factors, showed that individual evaluation of IPI parameters and inclusion of BAX and BCL-2 expression should be considered to improve predictive ability of IPI.

Telomerase activity is linked to continuous proliferation and implicated in development of HG-NHL. The study of telomerase activity, mRNA expression of telomerase components, and ARP in a preliminary series of HG-NHL showed that telomerase activity tended to be higher in p53 positive samples. Higher hTERT mRNA Expression tended to be associated with shorter overall survival. This observation should prompt investigation of telomerase activity and its components in larger clinical trials to confirm predictive significance.

List of scientific papers

I. Macnamara B, Palucka KA, Porwit-MacDonald A (1999). "Balance between proliferation and apoptosis in leukemic cell lines resistant to cytostatics. " Leuk Lymphoma 36(1-2): 179-89
https://pubmed.ncbi.nlm.nih.gov/10613463

II. Palucka KA, Knaust E, Xu D, Macnamara B, Porwit-Macdonald A, Gruber A, Peterson C, Bjorkholm M, Pisa P (1999). "Intraclonal heterogeneity in the in vitro daunorubicin-induced apoptosis in acute myeloid leukemia. " Leuk Lymphoma 32(3-4): 309-16
https://pubmed.ncbi.nlm.nih.gov/10037028

III. MacNamara B, Mazur J, Stromberg M, Christensson B (2001). "Indicators of cell growth and cell death indicators in highgrade non-Hodgkins lymphomas." (Submitted)

IV. MacNamara B, Mazur J, Stromberg M, Liliemark J (2001). "The significance of cell proliferation, apoptosis and expression of apoptosis-regulating proteins for disease course prediction in high-grade non-Hodgkins lymphomas." (Submitted)

V. MacNamara B, Wang W, Chen Z, Hou M, Mazur J, Gruber A, Porwit-MacDonald A (2001). "Telomerase activity in relation to pro- and anti-apoptotic protein expression in high grade non-Hodgkins lymphomas. " Haematologica 86(4): 386-93
https://pubmed.ncbi.nlm.nih.gov/11325644