Mitochondrial metabolism sustains DNMT3A-R882-mutant clonal haematopoiesis
Abstract
Abstract Somatic DNMT3A-R882 codon mutations drive the most common form of clonal haematopoiesis (CH) and are associated with increased acute myeloid leukaemia (AML) risk1,2. Preventing expansion of DNMT3A-R882-mutant haematopoietic stem/progenitor cells (HSPCs) may therefore avert progression to AML. To identify DNMT3A-R882-mutant-specific vulnerabilities, we conducted a genome-wide CRISPR screen on primary mouse Dnmt3a R882H/+ HSPCs. Among the 640 vulnerability genes identified, many were involved in mitochondrial metabolism, and metabolic flux analysis confirmed enhanced oxidative phosphorylation use in Dnmt3a R882H/+ versus Dnmt3a +/+ (WT) HSPCs. We selected citrate/malate transporter Slc25a1 and complex I component Ndufb11, for which pharmacological inhibitors are available, for downstream studies. In vivo administration of SLC25A1 inhibitor CTPI2 and complex I inhibitors IACS-010759 and metformin suppressed post-transplantation clonal expansion of Dnmt3a R882H/+, but not WT, long-term haematopoietic stem cells. The effect of metformin was recapitulated using a primary human DNMT3A-R882 CH sample. Notably, analysis of 412,234 UK Biobank participants showed that individuals taking metformin had a markedly lower prevalence of DNMT3A-R882-mutant CH, after controlling for potential confounders including glycated haemoglobin, diabetes and body mass index. Collectively, our data propose modulation of mitochondrial metabolism as a therapeutic strategy for prevention of DNMT3A-R882-mutant AML.
Article Details
Authors (42)
Malgorzata Gozdecka
Monika Dudek
Sean Wen
Muxin Gu
Richard J. Stopforth
Justyna Rak
Aristi Damaskou
Guinevere L. Grice
Matthew A. McLoughlin
Laura Bond
Rachael Wilson
George Giotopoulos
Vijaya Mahalingam Shanmugiah
Rula Bany Bakar
Eliza Yankova
Jonathan L. Cooper
Nisha Narayan
Sarah J. Horton
Ryan Asby
Dean C. Pask
Annalisa Mupo
Graham Duddy
Ludovica Marando
Theodoros Georgomanolis
Paul Carter
Amirtha Priya Ramesh
William G. Dunn
Clea Barcena
Paolo Gallipoli
Kosuke Yusa
Slavé Petrovski
Penny Wright
Pedro M. Quiros
Christian Frezza
James A. Nathan
Arthur Kaser
Siddhartha Kar
Konstantinos Tzelepis
Jonathan Mitchell
Margarete A. Fabre
Brian J. P. Huntly
George S. Vassiliou