PPM1D Mutations Drive Clonal Hematopoiesis in Response to Cytotoxic Chemotherapy.

Clonal hematopoiesis (CH), in which stem cell clones dominate blood production, becomes increasingly common with age and can presage malignancy development. The conditions that promote ascendancy of particular clones are unclear. We found that mutations in PPM1D (protein phosphatase Mn2+/Mg2+-dependent 1D), a DNA damage response regulator that is frequently mutated in CH, were present in one-fifth of patients with therapy-related acute myeloid leukemia or myelodysplastic syndrome and strongly correlated with cisplatin exposure. Cell lines with hyperactive PPM1D mutations expand to outcompete normal cells after exposure to cytotoxic DNA damaging agents including cisplatin, and this effect was predominantly mediated by increased resistance to apoptosis. Moreover, heterozygous mutant Ppm1d hematopoietic cells outcompeted their wild-type counterparts in vivo after exposure to cisplatin and doxorubicin, but not during recovery from bone marrow transplantation. These findings establish the clinical relevance of PPM1D mutations in CH and the importance of studying mutation-treatment interactions. VIDEO ABSTRACT.This work was supported by the Center Prevention and Research Institute of Texas (CPRIT) (RP160451 and R120501) and the NIH (DK092883, DK116428, S10RR024574, AI036211, P30 CA125123, and P30 CA016672). The Welch Foundation (G-0040), MD Anderson’s MoonShot Program, the Baylor Research Advocates for Student Scientists, and the BCM MSTP program also provided support. K.T. is supported by a Khalifa Physician Scientist Award, the Physician Scientist Program at MD Anderson, and a Leukemia SPORE Career Enhancement Award. G.V. is funded by a Cancer Research UK Senior Cancer Research Fellowship (C22324/A23015), the Kay Kendall Leukaemia Fund, Bloodwise, and core funding from the Sanger Institute (WT098051). We also thank the Samuel Waxman Cancer Research Foundation

Production of Sweet and High Biomass Sorghum Lines with Optimized Cell Wall Components for Increased Biofuel Bioconversion Yield

The current research focuses on the estimation of fibre content in sweet and high biomass sorghum lines for Production of sweet and high biomass sorghum lines with optimized cell wall components for increased biofuel bioconversion yield, through partially replicated experimental design for F3   populations based on BLUPs values; this study was carried out for four seasons (from postrainy 2020 to rainy 2022) to develop F3 populations of sweet and high-biomass bmr sorghum lines. The proximate fibre component analysis was done in the matured F3 populations by drying the plant samples and grinding them into a fine powder. Fibre quality components such as cellulose, hemicellulose, acid detergent fibre (ADF), acid detergent lignin (ADL), neutral detergent fibre (NDF), metabolizable energy (ME), nitrogen, in vitro organic matter digestibility (IVOMD), and ash, were assessed using Near-Infrared Reflectance Spectroscopy (NIRS). ICSV18003 had the lowest acid detergent fibre (ADF) percentage at 37.04%, while it also had the highest acid detergent lignin (ADL) percentage at 3.84%. The ash percentage was 3.73% in SSV84 × N609. Moreover, the bmr transferred lines of the F3 population exhibited higher levels of cellulose and hemicellulose, while lignin and ash content were decreased. This indicates that the bmr6 and bmr12 alleles can be confidently utilized in sorghum breeding for bioenergy production, as they meet the requirements for bioethanol production

An inhibitor of oxidative phosphorylation exploits cancer vulnerability

Metabolic reprograming is an emerging hallmark of tumor biology and an actively pursued opportunity in discovery of oncology drugs. Extensive efforts have focused on therapeutic targeting of glycolysis, whereas drugging mitochondrial oxidative phosphorylation (OXPHOS) has remained largely unexplored, partly owing to an incomplete understanding of tumor contexts in which OXPHOS is essential. Here, we report the discovery of IACS-010759, a clinical-grade small-molecule inhibitor of complex I of the mitochondrial electron transport chain. Treatment with IACS-010759 robustly inhibited proliferation and induced apoptosis in models of brain cancer and acute myeloid leukemia (AML) reliant on OXPHOS, likely owing to a combination of energy depletion and reduced aspartate production that leads to impaired nucleotide biosynthesis. In models of brain cancer and AML, tumor growth was potently inhibited in vivo following IACS-010759 treatment at well-tolerated doses. IACS-010759 is currently being evaluated in phase 1 clinical trials in relapsed/refractory AML and solid tumors