Clonal selection of hematopoietic stem cells after gene therapy for sickle cell disease

Author:

Spencer Chapman MichaelORCID,Cull Alyssa H.,Ciuculescu Marioara F.,Esrick Erica B.,Mitchell Emily,Jung Hyunchul,O’Neill Laura,Roberts Kirsty,Fabre Margarete A.,Williams Nicholas,Nangalia JyotiORCID,Quinton Joanne,Fox James M.,Pellin DaniloORCID,Makani Julie,Armant MyriamORCID,Williams David A.ORCID,Campbell Peter J.ORCID,Kent David G.ORCID

Abstract

AbstractGene therapy (GT) provides a potentially curative treatment option for patients with sickle cell disease (SCD); however, the occurrence of myeloid malignancies in GT clinical trials has prompted concern, with several postulated mechanisms. Here, we used whole-genome sequencing to track hematopoietic stem cells (HSCs) from six patients with SCD at pre- and post-GT time points to map the somatic mutation and clonal landscape of gene-modified and unmodified HSCs. Pre-GT, phylogenetic trees were highly polyclonal and mutation burdens per cell were elevated in some, but not all, patients. Post-GT, no clonal expansions were identified among gene-modified or unmodified cells; however, an increased frequency of potential driver mutations associated with myeloid neoplasms or clonal hematopoiesis (DNMT3A- and EZH2-mutated clones in particular) was observed in both genetically modified and unmodified cells, suggesting positive selection of mutant clones during GT. This work sheds light on HSC clonal dynamics and the mutational landscape after GT in SCD, highlighting the enhanced fitness of some HSCs harboring pre-existing driver mutations. Future studies should define the long-term fate of mutant clones, including any contribution to expansions associated with myeloid neoplasms.

Publisher

Springer Science and Business Media LLC

Subject

General Biochemistry, Genetics and Molecular Biology,General Medicine

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