Over the last decade, unparalleled advances have been made within the field of 'Philadelphia chromosome'-negative myeloproliferative neoplasms (MPN) regarding both disease pathogenesis and therapeutic targeting. The discovery of deregulated JAK-STAT signalling in MPN led to the rapid development of JAK inhibitor agents, targeting both mutated and wild-type JAK, which have significantly altered the therapeutic paradigm for patients with MPN. Although the largest population treated with these agents incorporates those with myelofibrosis, increasing data supports potential usage in other MPNs such as essential thromocythaemia and polycythaemia vera. Many MPNs are associated with a hyperinflammatory state and deregulation of immune homeostasis. Over the last few years, research has focused on attempting to decipher the complex and context-dependent changes that contribute to this immune deregulation. Moreover, very recent studies have demonstrated significant JAK inhibitor-mediated effects within the T cell, natural killer cell and dendritic cell compartments following exposure to JAK inhibitors. In parallel, case reports of infections occurring following exposure to ruxolitinib, many of which are atypical, have focused research efforts on delineating JAK inhibitor-associated immunological consequences. Within this review article, we will describe what is currently known about MPN-associated immune deregulation and JAK inhibitor-mediated immunomodulation.

Diagnostic criteria for hypoplastic myelodysplasic syndrome (h-MDS) have not been clearly established, making the differential diagnosis from other bone marrow failure syndromes (BMF) challenging. In this study, we aimed to delineate clinical, histopathological, and molecular features of h-MDS, based on a large and well-annotated cohort of patients with bone marrow (BM) hypocellularity. The study included 534 consecutive adult patients with hypocellular BM (278 h-MDS and 136 aplastic anemia), and 727 with normo-or hypercellular MDS (n-MDS). Comparison of clinical features of patients with h-MDS as defined by BM cellularity ≤25% (n = 204) or reduced age-adjusted cellularity (n = 74) did not reveal significant differences. We developed a diagnostic score to discriminate h-MDS from non-malignant BMF based on histological and cytological variables with the highest specificity for MDS (h-score). The information from chromosomal abnormalities and somatic mutation patterns was then integrated into a cyto-histological/genetic score (hg-score). This score was able to segregate two groups of h-MDS with a significantly different risk of blast progression (P < 0.001). The integration of cyto-histological and genetic features in adult patients with hypocellular BM facilitated segregation into two distinct groups, one with clinical and genetic features highly consistent with myeloid neoplasm, and one with features more consistent with non-malignant BMF.

SummaryDeregulated Hedgehog (Hh) signalling activity may be associated with a broad range of cancer types and hence has become an attractive target for therapeutic intervention. Although initial haematological interest focused on the therapeutic targeting of this pathway in chronic myeloid leukaemia), small molecule inhibitors targeting the Hh pathway are now being tested in a range of other myeloid disorders, including myelofibrosis, myelodysplasia and acute myeloid leukaemia. In this review we will evaluate the rationale for targeting of the Hh pathway in myeloid diseases and discuss the novel agents that have entered the clinical arena. We will discuss pre-clinical models, emerging clinical trial data, and suggest how these targeted therapies may address current unmet medical needs. Finally, we will explore potential limitations of these therapies due to the emergence of secondary resistance mechanisms and speculate on future developments within this arena.

The advent of new sequencing technologies has provided access to genome-wide markers which may be evaluated for their association with phenotypes. Recent studies have leveraged these technologies and sequenced hundreds and sometimes thousands of strains to improve the accuracy of genotype-phenotype predictions. Sequencing of thousands of strains is not practical for many research groups which argues for the formulation of new strategies to improve predictability using lower sample sizes and more cost-effective methods. We introduce here a novel computational algorithm called POPSICLE that leverages the local genetic variations to infer blocks of shared ancestries to construct complex evolutionary relationships. These evolutionary relationships are subsequently visualized using chromosome painting, as admixtures and as clades to acquire general as well as specific ancestral relationships within a population. In addition, POPSICLE evaluates the ancestral blocks for their association with phenotypes thereby bridging two powerful methodologies from population genetics and genome-wide association studies. In comparison to existing tools, POPSICLE offers substantial improvements in terms of accuracy, speed and automation. We evaluated POPSICLE's ability to find genetic determinants of Artemisinin resistance within P. falciparum using 57 randomly selected strains, out of 1,612 that were used in the original study. POPSICLE found Kelch, a gene implicated in the original study, to be significant (p-value 0) towards resistance to Artemisinin. We further extended this analysis to find shared ancestries among closely related P. falciparum, P. reichenowi and P. gaboni species from the Laverania subgenus of Plasmodium. POPSICLE was able to accurately infer the population structure of the Laverania subgenus and detected 4 strains from a chimpanzee in Koulamoutou with significant shared ancestries with P. falciparum and P. gaboni. We simulated 4 datasets to asses if these shared ancestries indicated a hybrid or mixed infections involving P. falciparum and P. gaboni. The analysis based on the simulated data and genomewide heterozygosity profiles of the strains indicate these are most likely mixed infections although the possibility of hybrids cannot be ruled out. POPSICLE is a java-based utility that requires no installation and can be downloaded freely from https://popsicleadmixture.sourceforge.io/ Author SummaryThe associations between genotypes and phenotypes have traditionally been performed using markers such as single nucleotide polymorphisms. Often, these markers are independently evaluated for their association with phenotypes. A genomic region is deemed significant if multiple markers with significance colocalize. However, multiple markers that are in linkage disequilibrium can sometimes work synergistically and contribute to phenotypic variations. These synergistic associations across markers and across subpopulations have traditionally been captured by population genetic approaches that determine local ancestries. We s...