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Clonal selection after gene therapy in sickle cell disease

While gene therapy (GT) provides a potentially curative treatment option for patients with sickle cell disease (SCD), the occurrence of myeloid malignancies in clinical trials has prompted concern. To interrogate potential mechanisms underlying increased cancer risk, we used hematopoietic stem cell (HSC) clonal tracking by whole genome sequencing (WGS) to map the somatic mutation and clonal landscape of 2,592 gene modified as well as unmodified single stem and progenitor cells from six SCD patients undergoing gene therapy (7-26 years old, average 12.7× depth). Pre-GT phylogenetic trees in SCD were highly polyclonal and mutation burdens per cell were elevated in some, but not all, patients. Post-GT, no clonal expansions were identified. However, an increased frequency of driver mutations associated with myeloid neoplasms or clonal hematopoiesis (DNMT3A- and EZH2-mutated clones in particular) were seen in both genetically modified and unmodified cells suggested positive selection of mutant clones during gene therapy. This work sheds light on the mutation landscape and HSC clonal dynamics in gene therapy for SCD and highlights enhanced fitness of some HSCs harboring pre-existing driver mutations following gene therapy. Future studies should define the long-term fate of mutant clones including any contribution to expansions associated with myeloid neoplasms.

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Studies are experimental investigations of a particular phenomenon, e.g., case-control studies on a particular trait or cancer research projects reporting matching cancer normal genomes from patients.

Study ID Study Title Study Type
EGAS00001007253 Cancer Genomics

This table displays only public information pertaining to the files in the dataset. If you wish to access this dataset, please submit a request. If you already have access to these data files, please consult the download documentation.

ID File Type Size Located in
EGAF00008083608 bam 2.8 GB
EGAF00008083609 bam 1.1 GB
EGAF00008083610 bam 1.5 GB
EGAF00008083611 bam 3.0 GB
EGAF00008083612 bam 3.0 GB
EGAF00008083613 bam 1.7 GB
EGAF00008083614 bam 1.7 GB
EGAF00008083615 bam 406.7 MB
EGAF00008083616 bam 3.0 GB
EGAF00008083617 bam 1.9 GB
EGAF00008083618 bam 2.0 GB
EGAF00008083619 bam 3.3 GB
EGAF00008083620 bam 1.1 GB
EGAF00008083621 bam 3.2 GB
EGAF00008083622 bam 2.0 GB
EGAF00008083623 bam 1.7 GB
EGAF00008083624 bam 1.4 GB
EGAF00008083625 bam 2.1 GB
EGAF00008083626 bam 2.6 GB
EGAF00008083627 bam 1.5 GB
EGAF00008083628 bam 2.5 GB
EGAF00008083629 bam 68.0 MB
EGAF00008083630 bam 2.9 GB
EGAF00008083631 bam 1.9 GB
24 Files (48.5 GB)