Mechanisms of stromal cells induced chemo-resistance in acute myeloid Leukemia

Abstract

Acute myeloid leukaemia (AML) is a haematopoietic malignancy of the myeloid lineage exposing rapid proliferation and accumulation of undifferentiated myeloid cells in the bone marrow (BM), thereby interfering with the production and maturation of normal blood cells. Although the prognosis of AML continues to be relatively poor, the treatment has improved substantially over the past few decades. Cytarabine (Ara-C) remains the backbone of AML treatment. It is a nucleoside analogue, which functions by inhibiting DNA synthesis. The chemo-resistance remains a significant issue following conventional chemotherapy when residual disease in the bone marrow BM relapses into a more resistance leukaemia. The interaction between AML with the BM stromal cells determines a protective environment that supports tumour development and resistance to conventional chemotherapy. This study showed that the HS5 cell line, which is a human marrow stromal cell line immortalised by transduction with the papilloma virus E6/E7, which encourages proliferation of haematopoietic progenitor cells and secretes soluble factors that protect leukaemic cell lines (HL-60 and K562) from Ara-C-induced toxicity. This leukaemia resistance is associated with a 2-fold reduction in intracellular Ara-CTP level (p<0.05), and a 4-fold increase in anthracycline efflux by Rhodamine 123 efflux (P<0.0001) in HL-60 cells. In contrast, K562 cells showed increased basal resistacne to Ara-C and daunorubicin (DNR), and less pronounced effect of conditioned medium (CM). To assess the possibility of a nutritional advantage of CM, protein estimation was performed by Bradford assay, and no significant increase in protein was observed for CM versus control medium (p>0.05), suggesting that the effect is mediated by specific soluble factors and downstream mechansims. New strategies to improve current therapeutic agents in AML are urgently needed to induce remission and to eliminate residual disease. It is necessary to search for specific inhibitors of the BM stroma-resistance pathway, to render existing treatments more effective.