Although there have been many new developments in the treatment of leukaemia with the use of new anti-leukaemic agents and stem cell transplantation, drug resistance and treatment failure remain a great challenge for the attending physician. Several studies have suggested that leukaemic stem cells (LSCs) play a pivotal role in chemoresistance and metastasis and the mechanisms by which these cells do so have also been elucidated. There is increasing evidence to show that there exists a large pool of therapeutic targets in LSCs and that the eradication of these cells is feasible with some promising results. This article gives an overview of different types of cancer stem cells (CSCs) derived from various types of leukaemia, the mechanisms by which LSCs contribute to drug resistance and metastasis and some recent advances in targeted therapy against LSCs.
"Although chemotherapy results in clinical remission for AML, drug resistance still represents a huge challenge to achieve effective treatment, especially in relapsed or refractory AML patients , . Cytostatic drug resistance occurs through different mechanisms, including induction of drug detoxification , the over-expression of oncogene or inactivation of tumor suppressor gene , , metabolic disturbance , , as well as existence of leukemia stem cells . Still, the exact mechanisms of drug resistance in leukemia have not been fully investigated. "
[Show abstract][Hide abstract] ABSTRACT: Nowadays, drug resistance still represents a major obstacle to successful acute myeloid leukemia (AML) treatment and the underlying mechanism is not fully elucidated. Here, we found that high expression of c-Myc was one of the cytogenetic characteristics in the drug-resistant leukemic cells. c-Myc over-expression in leukemic cells induced resistance to chemotherapeutic drugs, enhanced colony formation capacity and inhibited cell differentiation induced by all-trans retinoic acid (ATRA). Meanwhile, inhibition of c-Myc by shRNA or specific c-Myc inhibitor 10058-F4 rescued the sensitivity to cytotoxic drugs, restrained the colony formation ability and promoted differentiation. RT-PCR and western blotting analysis showed that down-regulation of C/EBPβ contributed to the poor differentiation state of leukemic cells induced by c-Myc over-expression. Importantly, over-expression of C/EBPβ could reverse c-Myc induced drug resistance. In primary AML cells, the c-Myc expression was negatively correlated with C/EBPβ. 10058-F4, displayed anti-proliferative activity and increased cellular differentiation with up-regulation of C/EBPβ in primary AML cells. Thus, our study indicated that c-Myc could be a novel target to overcome drug resistance, providing a new approach in AML therapy.
PLoS ONE 08/2014; 9(8):e105381. DOI:10.1371/journal.pone.0105381 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Acute myeloid leukaemia (AML) is a neoplasm originating in early haematopoietic progenitor cells. Each AML clone contains a subpopulation of leukaemic stem cells (LSCs). LSCs have the capacity to repopulate AML in NOD/SCID mice and regrow leukaemia in patients after remission period. LSCs are characterized by CD34+CD38-Lin-CD33+/-CD123+ immunophenotype. The currently available data show that LSCs play a pivotal role in drug resistance. Many studies and clinical trials are being conducted to eradicate LSCs using different forms of target therapy.
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