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Chronic myelogenous leukaemia (CML) can progress from a slow growing chronic phase to an aggressive blast crisis phase (1), but the molecular basis of this transition remains poorly understood. Here we have used mouse models of CML (2,3) to show that disease progression is regulated by the Musashi-Numb signalling axis (4,5). Specifically, we find that the chronic phase is marked by high levels of Numb expression whereas the blast crisis phase has low levels of Numb expression, and that ectopic expression of Numb promotes differentiation and impairs advanced-phase disease in vivo. As a possible explanation for the decreased levels of Numb in the blast crisis phase, we show that NUP98-HOXA9, an oncogene associated with blast crisis CML (6,7), can trigger expression of the RNA-binding protein Musashi2 (Msi2), which in turn represses Numb. Notably, loss of Msi2 restores Numb expression and significantly impairs the development and propagation of blast crisis CML in vitro and in vivo. Finally we show that Msi2 expression is not only highly upregulated during human CML progression but is also an early indicator of poorer prognosis. These data show that the Musashi-Numb pathway can control the differentiation of CML cells, and raise the possibility that targeting this pathway may provide a new strategy for the therapy of aggressive leukaemias., Chronic myelogenous leukaemia (CML) is initiated by the BCR-ABL translocation, which leads to myeloid cell expansion while allowing differentiation (8-11). Secondary translocations such as NUP98-HOXA9 or AML1-EVI1, or mutations in [...]

Autonomous and self-sustained oscillator circuits mediating the periodic induction of specific target genes are minimal genetic time-keeping devices found in the central and peripheral circadian clocks (1,2). They have attracted significant attention because of their intriguing dynamics and their importance in controlling critical repair (3), metabolic (4) and signalling pathway (5). The precise molecular mechanism and expression dynamics of this mammalian circadian clock are still not fully understood. Here we describe a synthetic mammalian oscillator based on an auto-regulated sense-antisense transcription control circuit encoding a positive and a time-delayed negative feedback loop, enabling autonomous, self-sustained and tunable oscillatory gene expression. After detailed systems design with experimental analyses and mathematical modelling, we monitored oscillating concentrations of green fluorescent protein with tunable frequency and amplitude by time-lapse microscopy in real time in individual Chinese hamster ovary cells. The synthetic mammalian clock may provide an insight into the dynamics of natural periodic processes and foster advances in the design of prosthetic networks in future gene and cell therapies., Synthetic gene circuits that emulate the expression dynamics of living systems provide new insights into the connectivity of genes and proteins in the postgenomic era(6) and they advance our understanding [...]

When Mark Lyte looked up from the podium at the 1992 American Society for Microbiology meeting in New Orleans, Louisiana, he saw two faces--and nearly 400 empty seats. Lyte, a [...]