Pevonedistat targets malignant cells in myeloproliferative neoplasms in vitro and in vivo via NFκB pathway inhibition

Targeted inhibitors of JAK2 (eg ruxolitinib) often provide symptomatic relief for myeloproliferative neoplasm (MPN) patients, but the malignant clone persists and remains susceptible to disease transformation. These observations suggest that targeting alternative dysregulated signaling pathways may provide therapeutic benefit. Previous studies identified NFκB pathway hyperactivation in myelofibrosis (MF) and secondary acute myeloid leukemia (sAML) that was insensitive to JAK2 inhibition. Here, we provide evidence that NFκB pathway inhibition via pevonedistat targets malignant cells in MPN patient samples as well as in MPN and patient-derived xenograft mouse models that are nonredundant with ruxolitinib. Colony forming assays revealed preferential inhibition of MF colony growth compared with normal colony formation. In mass cytometry studies, pevonedistat blunted canonical TNFα responses in MF and sAML patient CD34+ cells. Pevonedistat also inhibited hyperproduction of inflammatory cytokines more effectively than ruxolitinib. Upon pevonedistat treatment alone or in combination with ruxolitinib, MPN mouse models exhibited reduced disease burden and improved survival. These studies demonstrating efficacy of pevonedistat in MPN cells in vitro as well as in vivo provide a rationale for therapeutic inhibition of NFκB signaling for MF treatment. Based on these findings, a Phase 1 clinical trial combining pevonedistat with ruxolitinib has been initiated

METAL-POOR LITHIUM-RICH GIANTS IN THE RADIAL VELOCITY EXPERIMENT SURVEY

We report the discovery of eight lithium-rich field giants found in a high-resolution spectroscopic sample of over 700 metal-poor stars ([Fe/H] < -0.5) selected from the Radial Velocity Experiment survey. The majority of the Li-rich giants in our sample are very metal-poor ([Fe/H] ≲ -1.9), and have a Li abundance (in the form of 7Li), A(Li) = log (n(Li)/n(H)) + 12, between 2.30 and 3.63, well above the typical upper red giant branch (RGB) limit, A(Li) < 0.5, while two stars, with A(Li)∼1.7-1.8, show similar lithium abundances to normal giants at the same gravity. We further included two metal-poor, Li-rich g lobular cluster giants in our sample, namely the previously discovered M3-IV101 and newly discovered (in this work) M68-A96. This comprises the largest sample of metal-poor Li-rich giants to date. We performed a detailed abundance analysis of all stars, finding that the majority of our sample stars have elemental abundances similar to that of Li-normal halo giants. Although the evolutionary phase of each Li-rich giant cannot be definitively determined, the Li-rich phase is likely connected to extra mixing at the RGB bump or early asymptotic giant branch that triggers cool bottom processing in which the bottom of the outer convective envelope is connected to the H-burning shell in the star. The surface of a star becomes Li-enhanced as 7Be (which burns to 7Li) is transported to the stellar surface via the Cameron-Fowler mechanism. We discuss and discriminate among several models for the extra mixing that can cause Li production, given the detailed abundances of the Li-rich giants in our sample.14 page(s