Outcomes and characteristics of nonmelanoma skin cancers in patients with myeloproliferative neoplasms on ruxolitinib.

ABSTRACT: Nonmelanoma skin cancers (NMSCs) in ruxolitinib-treated patients with myeloproliferative neoplasms behave aggressively, with adverse features and high recurrence. In our cohort, mortality from metastatic NMSC exceeded that from myelofibrosis. Vigilant skin assessment, counseling on NMSC risks, and prospective ruxolitinib-NMSC studies are crucial.

Whole-genome sequence analysis of environmental Escherichia coli from the faeces of straw-necked ibis (Threskiornis spinicollis) nesting on inland wetlands.

Wildlife, and birds in particular, play an increasingly recognized role in the evolution and transmission of Escherichia coli that pose a threat to humans. To characterize these lineages and their potential threat from an evolutionary perspective, we isolated and performed whole-genome sequencing on 11 sequence types (STs) of E. coli recovered from the desiccated faeces of straw-necked ibis (Threskiornis spinicollis) nesting on inland wetlands located in geographically different regions of New South Wales, Australia. Carriage of virulence-associated genes was limited, and no antimicrobial resistance genes were detected, but novel variants of an insertion element that plays an important role in capturing and mobilizing antibiotic resistance genes, IS26, were identified and characterized. The isolates belonged to phylogroups B1 and D, including types known to cause disease in humans and animals. Specifically, we found E. coli ST58, ST69, ST162, ST212, ST446, ST906, ST2520, ST6096 and ST6241, and a novel phylogroup D strain, ST10208. Notably, the ST58 strain hosted significant virulence gene carriage. The sequences of two plasmids hosting putative virulence-associated factors with incompatibility groups I1 and Y, an extrachromosomal integrative/conjugative element, and a variant of a large Escherichia phage of the family Myoviridae, were additionally characterized. We identified multiple epidemiologically relevant gene signatures that link the ibis isolates to sequences from international sources, plus novel variants of IS26 across different sequence types and in different contexts.

Recurrent activating STAT5B N642H mutation in myeloid neoplasms with eosinophilia.

Determining the underlying cause of persistent eosinophilia is important for effective clinical management but remains a diagnostic challenge in many cases. We identified STAT5B N642H, an established oncogenic mutation, in 27/1715 (1.6%) cases referred for investigation of eosinophilia. Of the 27 mutated cases, a working diagnosis of hypereosinophilic syndrome (HES; n = 7) or a myeloid neoplasm with eosinophilia (n = 20) had been made prior to the detection of STAT5B N642H. Myeloid panel analysis identified a median of 2 additional mutated genes (range 0-4) with 4 cases having STAT5B N642H as a sole abnormality. STAT5B N642H was absent in cultured T cells of 4/4 positive cases. Individuals with SF3B1 mutations (9/27; 33%) or STAT5B N642H as a sole abnormality had a markedly better overall survival compared to cases with other additional mutations (median 65 months vs. 14 months; hazard ratio = 8.1; P < 0.001). The overall survival of STAT5B-mutated HES cases was only 30 months, suggesting that these cases should be reclassified as chronic eosinophilic leukemia, not otherwise specified (CEL-NOS). The finding of STAT5B N642H as a recurrent mutation in myeloid neoplasia with eosinophilia provides a new diagnostic and prognostic marker as well as a potential target for therapy.

Genetic variation at MECOM, TERT, JAK2 and HBS1L-MYB predisposes to myeloproliferative neoplasms.

Clonal proliferation in myeloproliferative neoplasms (MPN) is driven by somatic mutations in JAK2, CALR or MPL, but the contribution of inherited factors is poorly characterized. Using a three-stage genome-wide association study of 3,437 MPN cases and 10,083 controls, we identify two SNPs with genome-wide significance in JAK2(V617F)-negative MPN: rs12339666 (JAK2; meta-analysis P=1.27 × 10(-10)) and rs2201862 (MECOM; meta-analysis P=1.96 × 10(-9)). Two additional SNPs, rs2736100 (TERT) and rs9376092 (HBS1L/MYB), achieve genome-wide significance when including JAK2(V617F)-positive cases. rs9376092 has a stronger effect in JAK2(V617F)-negative cases with CALR and/or MPL mutations (Breslow-Day P=4.5 × 10(-7)), whereas in JAK2(V617F)-positive cases rs9376092 associates with essential thrombocythemia (ET) rather than polycythemia vera (allelic χ(2) P=7.3 × 10(-7)). Reduced MYB expression, previously linked to development of an ET-like disease in model systems, associates with rs9376092 in normal myeloid cells. These findings demonstrate that multiple germline variants predispose to MPN and link constitutional differences in MYB expression to disease phenotype.