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lation is therefore currently unknown. Taken together, the expression of genes in and around all the -globin LV insertions was MedChemExpress Tangeritin largely unperturbed. The stable copy number in all lineages, sustained HbF expression in red blood 2014 The American Society of Gene & Cell Therapy Safety of a globin lenti-vector in a macaque model H-P Kiem et PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19843565 al. 5 cells, and hematopoietic contribution from different clones at multiple time points without alterations in transcriptome suggest HSC clonal fluctuations. Furthermore, our analyses do not reflect clonal expansion or insertional mutagenesis. Similar RV marked HSC clonal fluctuations were shown in mice11 and in a human receiving cells genetically modified with an anti-HIV LV.40 In conclusion, long-term follow-up of a macaque transplanted with hematopoietic stem cells gene-modified with a human -globin-expressing LV demonstrates a relatively safe profile and potential therapeutic utility of this vector. These results are based on the characterization of stable hematopoietic reconstitution, polyclonal gene-modified hematopoiesis, and stable transgene expression. Absence of insertions leading to pronounced clonal outgrowth or transcriptional dysregulation has promising implications for clinical LV-based gene therapy. ~~ The chromosomal passenger hypothesis proposed that diverse mitotic events, including chromosome segregation and cytokinesis, could be coordinated by a set of proteins that localized to chromosomes during early mitosis, before transferring to the spindle midzone during late mitosis1. Interest in these proteins took off when it was realized that INCENP, the first passenger protein identified2, formed a complex with Aurora B kinase, a protein essential for accurate cell division3, 4. It is now known that the chromosomal passenger complex is composed of four subunits: the enzymatic component Aurora B and the three regulatory and targeting components INCENP, Survivin and Borealin 57. Dynamic changes in CPC localisation throughout mitosis ensure the effective and spatially restricted phosphorylation of substrates involved in chromosome condensation, correction of erroneous kinetochore-microtubule attachments, activation of the spindle assembly checkpoint, and cytokinesis. When INCENP, Survivin or Borealin localisation and/or function are perturbed, the others do not localize properly, Aurora B activity is diminished and proper cell division is compromised812. A fifth putative passenger protein, the GEF TD-60/Rcc213 does not stably associate with the CPC and its function in mitosis is not yet understood. Here we discuss current knowledge concerning the structure, activation, localisation and targets of the CPC in mitosis, focusing on the regulation of the complex by other cellular Correspondence to: Mar Carmena; Hironori Funabiki; William C. Earnshaw. 4Co-equal first authors Carmena et al. Page 2 activities and revealing how this regulation changes as mitosis progresses. Due to space constraints, we will not cover the functions of the CPC in meiosis. Our aim is to show how this critical signaling module is integrated structurally and mechanistically with the global cell cycle machinery, and with the intricate structures at kinetochores and the central spindle. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript Composition and Structure of the CPC Biochemical and structural studies reveal that the CPC is composed of a localisation module and a kinase module linked togethe