Outcomes of global coagulation assays in patients with Philadelphia-negative myeloproliferative neoplasms with respect to genetic determinants of clonal progression

Classical myeloproliferative neoplasms (MPNs) are hematopoietic stem cell disorders that manifest with inflammation, promotion of atherosclerosis, hypercoagulability, fibrosis, and clonal evolution. The complex biological background lends itself to multi-omics studies. We have previously shown that reduced platelet fibrinogen receptor (PFR) expression may follow hyperactivation of plasma-dependent mechanisms, such as tissue factor (TF) release, unbalanced thrombin generation, involvement of protease-activated receptors (PARs). Acetylsalicylic acid (ASA) helped to restore the expression of PFRs. In this study, we enrolled 53 MPN patients, subjecting them to advanced genetic testing (panel of 30 genes in NGS), global coagulation testing (Rotational Thromboelastometry - ROTEM) and cytofluorometric determination of PFRs. ROTEM parameters appear to differ considerably depending on the type of pathology under investigation, cell count, and selected mutations. Essential thrombocythemia (ET) and CALR mutation appear to correlate with increased efficiency of both classical coagulation pathways, with significantly more contracted clot formation times (CFTs). In contrast, primary myelofibrosis (PMF) and polycythemia vera (PV) show greater imbalances in the hemostatic system. PV, probably due to its peculiar hematological features, shows a lengthening of the CFT and, at the same time, a selective contraction of parameters in INTEM with the increase of platelets and white blood cells. PMF - in contrast - seems to exploit the extrinsic pathway more to increase cell numbers. The presence of DNMT3A mutations is associated with reduced clotting time (CT) in EXTEM, while ASXL1 causes reduced maximal lysis (ML). EZH2 could be responsible for the elongation of CFT in INTEM assay. In addition, increased PFR expression is associated with history of hemorrhage and sustained CT time in FIBTEM under ASA prophylaxis. Our findings corroborate the existing models on the connection between fibrosis, genetic complexity, clonal progression, and hypercoagulability. Global coagulation assays and PFR expression are potentially useful tools for dynamic evaluation of treatments’ outcomes.

QTL mapping identifies novel major loci for ear fasciation, ear prolificacy and tillering in maize (ZEA MAYS L.)

Maize ear fasciation originates from excessive or abnormal proliferation of the ear meristem and usually manifests as multiple-tipped ear, ear flatness and/or disordered kernel arrangement. Ear prolificacy expresses as multiple ears per node. Both traits can affect grain yield. In this study, the genetic control of the two traits was analyzed using two recombinant inbred lines (RIL) populations (B73 × Lo1016 and Lo964 × Lo1016) with Lo1016 and Lo964 as donors of ear fasciation and prolificacy, respectively. Four ear fasciation-related traits (ear fasciation, kernel distribution and ear ovality indexes and ratio of ear diameters), number of kernel rows, ear prolificacy and number of tillers were phenotyped in multi-year field experiments. Ear fasciation traits and number of kernel rows showed relatively high heritability (h2 > 0.5) except ratio of ear diameters, and showed correlation. Prolificacy and tillering h2 ranged 0.41 - 0.78 and did not correlate. QTL mapping identified four QTL for ear fasciation, on chr. 1 (two QTLs), 5 and 7, the latter two overlapping with QTLs for number of kernel rows. However, the strongest effect QTL for number of kernel rows mapped on chr. 2 independently from ear fasciation. Four and five non-overlapping QTLs were mapped for ear prolificacy and tillering, respectively. Two ear fasciation QTLs from this study, qFas1.2 and qFas7, overlapped with formerly known fasciation QTLs and spanned candidate genes expressed in ear meristems namely compact plant2 and ramosa1. Our study identified novel ear fasciation, ear prolificacy and tillering loci which are unexpectedly still segregating in elite maize materials, and provides foundation for genomics-assisted breeding for yield components