Cell death mechanisms of anti-cancer agents and treatment response in acute leukemia

Acute leukemia (AL) is a fatal disease, which causes rapid death in the absence of appropriate chemotherapeutic intervention. Long-term survival rates vary from 80% in childhood lymphoblastic AL (ALL) to 10-20% in adult myeloid AL (AML). Failures to achieve complete remission (CR) and relapses are mainly due to chemoresistance of the malignant cells.

In this thesis, the molecular mechanisms of cell death as induced by two antileukemia agents, doxorubicin (DXR) and the glucocorticoid dexamethasone (Dex), were investigated. The monitoring of malignant cell clearance from the bone marrow of patients during treatment for leukemia complements molecular studies with the main goal of improving prognosis in AL. Finally, pre- and post-chemotherapy levels of dendritic cells (M) were examined. DCs constitute a complex system orchestrating the immune response but have not been extensively studied in AL patients.

Sequentially activated caspase-2, PKCδ and JNK were defined as the key components in DXR-induced apoptosis in AL (Paper 1). Dex-induced cell death in ALL cell lines and primary leukemia cells was found to occur through P13K/Akt-dependent autophagy: a novel caspase-independent cell death pathway. There was a positive correlation between ex vivo Dex-sensitivity of ALL blasts and an early treatment response of patients with ALL (Paper 11). Young adult AML patients, who have detectable minimal residual disease at the first CR and/or at the end of post-remission chemotherapy, were demonstrated to have a dismal prognosis and to benefit from stem cell transplantation (Paper III). Children with ALL at diagnosis were found to have a profound deficiency of DCs. This deficiency was more severe in B-ALL than in T-ALL. The myeloid DC subset was affected by cytostatic therapy more than the plasmocytoid DC subset (Paper IV).

Studies included this thesis may help to refine the selection of individual therapeutic strategies in the treatment of AL patients and thus to improve long-term outcome. The study also elucidates some mechanisms of drug resistance and identifies new prognostic factors for AL patients.

List of scientific papers

I. Panaretakis T, Laane E, Pokrovskaja K, Bjorklund AC, Moustakas A, Zhivotovsky B, Heyman M, Shoshan MC, Grander D (2005). Doxorubicin requires the sequential activation of caspase-2, protein kinase Cdelta, and c-Jun NH2-terminal kinase to induce apoptosis. Mol Biol Cell. 16(8): 3821-31.
https://pubmed.ncbi.nlm.nih.gov/15917298

II. Laane E, Panaretakis T, Pokrovskaja K, Buentke E, Hultenby K, Concoran M, Soderhall S, Heyman M, Zhivotovsky B, Porwit A, Grandér D (2006). Glucocorticoid induced cell death in ALL cells involves autophagy and the modulation of the Bcl-2 family members. [Manuscript]

III. Laane E, Derolf AR, Bjorklund E, Mazur J, Everaus H, Soderhall S, Bjorkholm M, Porwit-MacDonald A (2006). The effect of allogeneic stem cell transplantation on outcome in younger acute myeloid leukemia patients with minimal residual disease detected by flow cytometry at the end of post-remission chemotherapy.
https://pubmed.ncbi.nlm.nih.gov/16769587

IV. Laane E, Bjorklund E, Mazur J, Lonnerholm G, Soderhall S, Porwit A (2006). Dendritic cell regeneration in bone marrow and peripheral blood of children treated for acute lymphoblastic leukemia by NOPHO ALL-2000 protocol. [Manuscript]