In vivo tumorigenicity of the 20q11.21 amplicon in an engraftment model of hPSCs and differentiated liver cells

Human pluripotent stem cells (hPSCs) are a promising source of somatic cells for clinical applications and disease modelling. However, during culture they accumulate genetic aberrations such as amplification of 20q11.21 which occurs in approximately 20% of extensively cultured hPSC lines and confers a BCL2L1-mediated survival advantage. During the production of the large number of cells required for transplantation and therapy these aberrations may become unavoidable which has important safety implications for therapies and may also impact upon disease modelling. Presently, these risks are poorly understood; whilst it is apparent that large-scale genetic aberrations can pose an oncogenic risk, the risks associated with smaller, more insidious changes have not been fully explored. In this report, the effects of engraftment of human embryonic stem cells (hESCs) and hESC-derived hepatocyte-like cells (HLCs) with and without amplification of the 20q11.21 minimal amplicon and isochromosome 20q (i20q) in SCID-beige mice are presented. The cells were tracked in vivo using a luminescent reporter over a period of approximately four months. Intrasplenic injection of hESCs showed greater engraftment potential and the formation of more severely disruptive lesions in the liver and spleen of animals injected with cells containing 20q11.21 compared with i20q and wild type. HLCs with 20q11.21 engrafted more successfully and formed more severely disruptive lesions than wild type cells or cells with i20q. These results reinforce the notion that karyotyping of therapeutic hPSC is required for transplant, and suggest that screening for known common aberrations is necessary. Further work to identify commonly arising genetic aberrations should be performed and routine screening for hPSCs intended for therapeutic use should be used

Geochronology in the southern Midyan terrane: a review of constraints on the timing of magmatic pulses and tectonic evolution in a northwestern part of the Arabian Shield

© 2017 Taylor & Francis The southern Midyan terrane is a composite Tonian to Ediacaran tectonostratigraphic crustal block in the northern Arabian Shield that prior to Red Sea opening was contiguous with coeval rocks in the Eastern Desert of Egypt and Sinai. Ion microprobe (sensitive high-resolution ion microprobe [SHRIMP]) dating of 12 rock samples described here and the results of other dating programmes establish a clear timeframe for depositional, intrusive, and structural events in the region and provide a chronology of tectonism in this part of the Arabian-Nubian Shield. Deposition of Zaam and Bayda group volcanosedimentary rocks and emplacement of mafic-ultramafic complexes and TTG-type diorite, tonalite, and granodiorite denote formation of the Tonian (780–715 Ma) Zaam arc and fore-arc ophiolite above a possible west-dipping subduction system in the southern part of the Midyan terrane. Convergence with the Hijaz terrane farther south and obduction of ophiolite nappes resulted by ~700 Ma in development of the Yanbu suture. Ongoing or a new subduction system led to a ~705–660 Ma Cryogenian pulse of magmatism represented by I-type calc-alkaline diorite, granodiorite, and granite that have volcanic-arc and syn-collisional granite affinities. This was followed, after a brief end-Cryogenian hiatus, by a 635–~570 Ma period of Ediacaran magmatism marked by monzogranite, syenogranite, and minor gabbro and diorite. These rocks are reported to have within-plate to volcanic-arc and syncollision chemical characteristics but their precise tectonic setting is uncertain. Structurally, the intrusions are diapiric and were evidently emplaced in an extensional regime consistent with an overlap between intrusion and Najd faulting associated, at this time, with transpressional collision and northward extension through much of the ANS. Terminal magmatism in the southern Midyan terrane postdated cessation of Najd faulting at ~575 Ma and resulted in the emplacement of undeformed within-plate A-type alkali-feldspar granites and mafic (lamprophyre) and felsic dikes