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Although xenografts are one of the most attractive strategies for overcoming the shortage of organ donors, cellular rejection by macrophages is a substantial impediment to this procedure. It is well known that macrophages mediate robust immune responses in xenografts. Macrophages also express various inhibitory receptors that regulate their immunological function. Recent studies have shown that the overexpression of inhibitory ligands on porcine target cells results in the phosphorylation of tyrosine residues on intracellular immunoreceptor tyrosine-based inhibitory motifs on macrophages, leading to the suppression of xenogenic rejection by macrophages. It has also been reported that myeloid-derived suppressor cells, a heterogeneous population of immature myeloid cells, suppress not only NK and cytotoxic T lymphocyte cytotoxicity but also macrophage-mediated cytotoxicity. This review is focused on the recent findings regarding strategies for inhibiting xenogenic rejection by macrophages.

Juvenile myelomonocytic leukemia (JMML) is a myeloproliferative neoplasm (MPN) of childhood with a poor prognosis. Mutations in NF1, NRAS, KRAS, PTPN11 and CBL occur in 85% of patients, yet there are currently no risk stratification algorithms capable of predicting which patients will be refractory to conventional treatment and therefore be candidates for experimental therapies. In addition, there have been few other molecular pathways identified aside from the Ras/MAPK pathway to serve as the basis for such novel therapeutic strategies. We therefore sought to genomically characterize serial samples from patients at diagnosis through relapse and transformation to acute myeloid leukemia in order to expand our knowledge of the mutational spectrum in JMML. We identified recurrent mutations in genes involved in signal transduction, gene splicing, the polycomb repressive complex 2 (PRC2) and transcription. Importantly, the number of somatic alterations present at diagnosis appears to be the major determinant of outcome.

The RASopathies constitute a diverse group of congenital disorders characterised by short stature, cardiac anomalies, distinctive facial features, predisposition to developing juvenile myelomonocytic leukaemia (JMML) and germline mutations in the Ras-mitogen activated protein kinase (MAPK) pathway.1 We recently described the genomic landscape of JMML, which can arise in the context of germline or somatic lesions in the Ras-MAPK pathway and identified somatic RRAS2 mutations as a novel lesion in JMML.2 We thus hypothesised that germline RRAS2 mutations could be an additional cause of Noonan syndrome (NS) and therefore screened 116 patients with NS who had no other identified lesions. No recurrent mutations were found in RRAS2 . Autosomal dominant germline mutations in a variety of Ras-MAPK pathway genes, including PTPN11, SOS1, KRAS, HRAS, MAP2K1, MAP2K2, NRAS, RAF1, CBL, NF1, SPRED1, BRAF, SHOC2, …

Nat. Genet. 47, 1326–1333 (2015); published online 12 October 2015; corrected after print 7 December 2015 In the version of this article initially published, two patients were stated on page 5 to have been excluded owing to insufficient follow-up data. These patients were included in the final analysis, but two additional patients were excluded owing to the presence of Noonan syndrome.