Clonal hematopoiesis in sickle cell disease

Curative gene therapies for sickle cell disease (SCD) are currently undergoing clinical evaluation. However, the occurrence of several myeloid malignancy cases in these trials has prompted safety concerns. Individuals with SCD are predisposed to myeloid malignancies, but the underlying causes remain undefined. Clonal hematopoiesis (CH) is a pre-malignant condition that also confers significant predisposition to myeloid cancers. While it has been speculated that CH may play a role in SCD-associated cancer predisposition, no data addressing this issue have been reported. Here, we leverage 74,190 whole-genome sequences to robustly study CH in SCD. While we have sufficient power to detect increased rates of CH, we find no variation in rate or clone properties between individuals affected by SCD and controls. These results should help guide ongoing efforts that seek to better define the risk factors underlying myeloid malignancy predisposition in SCD and help ensure that curative therapies can be more safely applied.