Oncogenically active MYD88 mutations in human lymphoma

The activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) remains the least curable form of this malignancy despite recent advances in therapy. Constitutive nuclear factor (NF)-κB and JAK kinase signalling promotes malignant cell survival in these lymphomas, but the genetic basis for this signalling is incompletely understood. Here we describe the dependence of ABC DLBCLs on MYD88, an adaptor protein that mediates toll and interleukin (IL)-1 receptor signalling, and the discovery of highly recurrent oncogenic mutations affecting MYD88 in ABC DLBCL tumours. RNA interference screening revealed that MYD88 and the associated kinases IRAK1 and IRAK4 are essential for ABC DLBCL survival. High-throughput RNA resequencing uncovered MYD88 mutations in ABC DLBCL lines. Notably, 29% of ABC DLBCL tumours harboured the same amino acid substitution, L265P, in the MYD88 Toll/IL-1 receptor (TIR) domain at an evolutionarily invariant residue in its hydrophobic core. This mutation was rare or absent in other DLBCL subtypes and Burkitt's lymphoma, but was observed in 9% of mucosa-associated lymphoid tissue lymphomas. At a lower frequency, additional mutations were observed in the MYD88 TIR domain, occurring in both the ABC and germinal centre B-cell-like (GCB) DLBCL subtypes. Survival of ABC DLBCL cells bearing the L265P mutation was sustained by the mutant but not the wild-type MYD88 isoform, demonstrating that L265P is a gain-of-function driver mutation. The L265P mutant promoted cell survival by spontaneously assembling a protein complex containing IRAK1 and IRAK4, leading to IRAK4 kinase activity, IRAK1 phosphorylation, NF-κB signalling, JAK kinase activation of STAT3, and secretion of IL-6, IL-10 and interferon-β. Hence, the MYD88 signalling pathway is integral to the pathogenesis of ABC DLBCL, supporting the development of inhibitors of IRAK4 kinase and other components of this pathway for the treatment of tumours bearing oncogenic MYD88 mutations.     

Substance P in medullary carcinoma of the thyroid.

High levels of substance P-like immunoreactivity were demonstrated by radioimmunoassay in the plasma and tumour of a patient with a medullary carcinoma of the thyroid.     

Tamarix aphylla : a newly invasive tree in southern Nevada

In the southwestern United States, the nonnative athel pine ( Tamarix aphylla ) was presumed to be sterile and therefore not as likely to spread as its widely distributed, nonnative congener, T. ramosissima . However, at Lake Mead National Recreation Area (LMNRA) in southern Nevada, populations of T. aphylla have recently spread beyond their limited pre-1990 distribution and now form extensive monospecific stands. Over a 3-year period, we quantified seed production and germination from 60 T. aphylla trees at LMNRA. The annual mean seed production period was 50.6 days, and the mean potential germination (under laboratory conditions) was 22%, indicating that T. aphylla trees at LMNRA are capable of sexual reproduction in southern Nevada. No seeds germinated in field experiments, apparently because of high soil salt levels. However, seedling regeneration is becoming increasingly common at LMNRA. Tamarix aphylla trees occupied a distinct zone along the shoreline of Lake Mead, above T. ramosissima in elevation and below native Larrea tridentata communities, suggesting either competitive exclusion or differential resource utilization. The T. aphylla zone tended to have the highest mean values for total vegetation cover, leaf litter depth, soil salinity, soil moisture, pH, total Kjeldahl nitrogen, and soil organic matter. The capacity for sexual reproduction of this alien plant, combined with a suite of characteristics shared with the invasive T. ramosissima (e.g., drought tolerance and copious saline leaf litter), makes T. aphylla a potentially invasive species along the shores of LMNRA and other mesic areas in the desert Southwest.