ABSTRACT
PURPOSE OF REVIEW: Leukemia carrying mutation of the mixed-lineage leukemia (MLL) gene is particularly refractory to current treatment, and is associated with frequent relapse. We will review the biology of MLL leukemia, and explore the potential of targeting multiple signaling pathways deregulated in MLL leukemic stem cells (LSCs). RECENT FINDINGS: Glycogen synthase kinase 3 (GSK3) plays a critical role in mediating Hox/MEIS1 transcriptional program and its inhibition shows promise in suppressing leukemia carrying MLL fusions or aberrant Hox expression. However, recent evidence indicates that GSK3 inhibition can be overcome by hyperactivation of the canonical Wnt signaling pathway in MLL LSCs, whereas suppression of ß-catenin resensitizes MLL LSCs to the GSK3 inhibitor treatment. These results suggest a differential GSK3 dependence in different subsets of leukemic populations during disease development. SUMMARY: On the basis of the results from preclinical model studies, a combination treatment targeting both GSK3 and the canonical Wnt signaling pathway emerges as a promising avenue to eradicate MLL LSCs. Future effort in identifying the key tractable components along these signaling pathways will be critical for the development of effective inhibitors to target this aggressive disease.
Subject(s)
Glycogen Synthase Kinase 3/antagonists & inhibitors , Leukemia, Biphenotypic, Acute/metabolism , Neoplastic Stem Cells/metabolism , Wnt Proteins/metabolism , Wnt Signaling Pathway/physiology , beta Catenin/metabolism , Animals , Cell Line, Tumor , Cell Transformation, Neoplastic/metabolism , Glycogen Synthase Kinase 3/physiology , Humans , Leukemia, Biphenotypic, Acute/pathology , Leukemia, Biphenotypic, Acute/therapy , Molecular Targeted Therapy , Neoplastic Stem Cells/pathologyABSTRACT
The efficacy of tyrosine kinase (TK) inhibitors on non-cycling acute myeloid leukaemia (AML) cells, previously shown to have potent tumourigenic potential, is unknown. This pilot study describes the first attempt to characterize non-cycling cells from a small series of human FMS-like tyrosine kinase 3 (FLT3) mutation positive samples. CD34+ AML cells from patients with FLT3 mutation positive AML were cultured on murine stroma. In expansion cultures, non-cycling cells were found to retain CD34+ expression in contrast to dividing cells. Leukaemic gene rearrangements could be detected in non-cycling cells, indicating their leukaemic origin. Significantly, the FLT3-internal tandem duplication (ITD) mutation was found in the non-cycling fraction of four out of five cases. Exposure to the FLT3-directed inhibitor TKI258 clearly inhibited the growth of AML CD34+ cells in short-term cultures and colony-forming unit assays. Crucially, non-cycling cells were not eradicated, with the exception of one case, which exhibited exquisite sensitivity to the compound. Moreover, in longer-term cultures, TKI258-treated non-cycling cells showed no growth impairment compared to treatment-naive non-cycling cells. These findings suggest that non-cycling cells in AML may constitute a disease reservoir that is resistant to TK inhibition. Further studies with a larger sample size and other inhibitors are warranted.