The Yeast Protein Kinase Sch9 Functions as a Central Nutrient-Responsive Hub That Calibrates Metabolic and Stress-Related Responses

Funding Information: This research was funded by the Canton of Fribourg and the Swiss National Science Foundation (310030_166474/184671) to C.D.V., the Fonds Wetenschappelijk Onderzoek (FWO)-Vlaanderen (G069413, G0C7222N) and KU Leuven (C14/17/063, C14/21/095) to J.W., Biotechnology and Biological Sciences Research Council (BB/V016334/1) to RH, and Portuguese National funds, through the Foundation for Science and Technology (FCT)—project UIDB/50026/2020 and UIDP/50026/2020 for P.L. and B.S.-M. B.S.-M. was funded by FCT, grant number DL 57/2016.Peer reviewedPublisher PD

ZAP-70 expression, as detected by immunohistochemistry on bone marrow biopsies from early-phase CLL patients, is a strong adverse prognostic factor.

Zeta-associated protein-70 (ZAP-70), mostly assessed by flowcytometry (FC), recently emerged as reliable prognostic factor in chronic lymphocytic leukaemia (CLL) at presentation. We evaluated ZAP-70 expression in 156 CLL patients by immunohistochemistry (IHC) on formalin-fixed bone marrow (BM) biopsies at diagnosis. At presentation, 117 patients (75%) were with Binet stage A, 27 (17%) stage B and 12 (8%) stage C. Median follow-up was 61 months (range 6–242). ZAP-70 was expressed in neoplastic lymphocytes of 69 patients (44%). Concordance between ZAP-70 by IHC and ZAP-70 by FC, immunoglobulin heavy chain variable genes (IGHV) mutational status and CD38 expression was found in 41/46 (89%), 41/49 (80%) and in 60/88 (68%) tested cases, respectively. ZAP-70 expression significantly correlated with advanced Binet stage (B–C), diffuse BM infiltration, increased lactate dehydrogenase (LDH) and b2-microglobulin serum levels and lymphocyte doubling time o12 months. ZAP-70 positivity was significantly related to poorer time to progression (median 16 months vs 158 of ZAP-70-negative cases) (Po0.0001) and overall survival (median 106 months vs not reached) (P¼0.0002); this correlation was confirmed at multivariate analysis. ZAP-70 expression correlated with poorer outcome also when evaluated only in the 117 stage A patients. In conclusion, immunohistological detection of ZAP-70 on formalin-fixed BM biopsies at diagnosis appears a useful methodological approach to identify patients with poor prognosis in CLL

The nutrient-responsive CDK Pho85 primes the Sch9 kinase for its activation by TORC1

Funding: Research was funded by fellowships of FWO-Vlaanderen (Fonds Wetenschappelijk Onderzoek) to RG and EE, a grant of the Biotechnology and Biological Sciences Research Council (BB/V016334/1) to RH, grants of the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) through Project-ID 403222702, SFB 1381, TP B08 to SR and RO 1028/5-2 to SR, the Germany’s Excellence Strategy, (BIOSS) EXC 949 and CIBSS (EXC 2189) to SR, the DFG projects UN111/10-2 and SFB 1557, TP14 to CU, the Swiss National Science Foundation (310030_166474/184671) to CDV, FWO-Vlaanderen (G069413, G0C7222N) to JW and KU Leuven (C14/17/063, C14/21/095) to JW. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD