ABSTRACT
The purpose of this retrospective study was to study the correlation between donor age (DA) and non-relapse mortality (NRM) and relapse incidence (RI) among patients treated with allogeneic hematopoietic cell transplantation (aHCT) for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) in a single Canadian center. Data from 125 consecutive patients transplanted with a matched related or unrelated donor between 2015 and 2020 were analyzed using multivariable models. After a median follow-up of 2.8 years, the cumulative incidences of NRM and relapse were 19% and 35% at 5 years. Despite being independently associated with NRM and relapse-free survival (RFS), DA was not associated with RI. The independent determinants of NRM in addition to DA were patient age and hematopoietic cell transplantation comorbidity index (HCT-CI), independently of donor kinship. The effect of DA on NRM was found to be significantly increased over the age of 50 years. DA was not associated with incidence of acute graft-versus-host disease (aGVHD) but showed an association with the occurrence of chronic GVHD (cGVHD). In conclusion, younger donors should be favored to limit NRM and increase RFS in HLA-matched aHCT. The etiological mechanisms behind the association of DA with higher NRM remain to be elucidated.
Subject(s)
Graft vs Host Disease , Hematopoietic Stem Cell Transplantation , Leukemia, Myeloid, Acute , Myelodysplastic Syndromes , Canada/epidemiology , Graft vs Host Disease/etiology , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , Leukemia, Myeloid, Acute/complications , Leukemia, Myeloid, Acute/therapy , Middle Aged , Myelodysplastic Syndromes/therapy , Recurrence , Retrospective Studies , Transplantation, Homologous/adverse effectsABSTRACT
The essential Rcl1p and Bms1p proteins form a complex required for 40S ribosomal subunit maturation. Bms1p is a GTPase and Rcl1p has been proposed to catalyse the endonucleolytic cleavage at site A2 separating the pre-40S and pre-60S maturation pathways. We determined the 2.0 Å crystal structure of Bms1p associated with Rcl1p. We demonstrate that Rcl1p nuclear import depends on Bms1p and that the two proteins are loaded into pre-ribosomes at a similar stage of the maturation pathway and remain present within pre-ribosomes after cleavage at A2. Importantly, GTP binding to Bms1p is not required for the import in the nucleus nor for the incorporation of Rcl1p into pre-ribosomes, but is essential for early pre-rRNA processing. We propose that GTP binding to Bms1p and/or GTP hydrolysis may induce conformational rearrangements within the Bms1p-Rcl1p complex allowing the interaction of Rcl1p with its RNA substrate.
Subject(s)
GTP-Binding Proteins/chemistry , GTP-Binding Proteins/metabolism , Nuclear Proteins/chemistry , Nuclear Proteins/metabolism , RNA Processing, Post-Transcriptional , RNA, Ribosomal/metabolism , RNA-Binding Proteins/chemistry , RNA-Binding Proteins/metabolism , Saccharomyces cerevisiae Proteins/chemistry , Saccharomyces cerevisiae Proteins/metabolism , Active Transport, Cell Nucleus , Cell Nucleus/metabolism , Gene Expression Regulation, Fungal , Guanosine Triphosphate/metabolism , Nuclear Proteins/genetics , Point Mutation , Protein Binding , Protein Interaction Domains and Motifs , RNA Precursors/metabolism , Ribosomes/metabolism , Saccharomyces cerevisiae Proteins/geneticsABSTRACT
We provide evidence that a central player in ribosome synthesis, the ribonucleic acid helicase Prp43p, can be activated by yeast Gno1p and its human ortholog, the telomerase inhibitor PINX1. Gno1p and PINX1 expressed in yeast interact with Prp43p and the integrity of their G-patch domain is required for this interaction. Moreover, PINX1 interacts with human PRP43 (DHX15) in HeLa cells. PINX1 directly binds to yeast Prp43p and stimulates its adenosine triphosphatase activity, while alterations of the G patch abolish formation of the PINX1/Prp43p complex and the stimulation of Prp43p. In yeast, lack of Gno1p leads to a decrease in the levels of pre-40S and intermediate pre-60S pre-ribosomal particles, defects that can be corrected by PINX1 expression. We show that Gno1p associates with 90S and early pre-60S pre-ribosomal particles and is released from intermediate pre-60S particles. G-patch alterations in Gno1p or PINX1 that inhibit their interactions with Prp43p completely abolish their function in yeast ribosome biogenesis. Altogether, our results suggest that activation of Prp43p by Gno1p/PINX1 within early pre-ribosomal particles is crucial for their subsequent maturation.
