Clonal hematopoiesis in sickle cell disease.

Journal Article (Clinical Trial;Journal Article;Multicenter Study)

BACKGROUNDCurative gene therapies for sickle cell disease (SCD) are currently undergoing clinical evaluation. The occurrence of myeloid malignancies 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 premalignant 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, limited data addressing this issue have been reported.METHODSHere, we leveraged 74,190 whole-genome sequences to robustly study CH in SCD. Somatic mutation calling methods were used to assess CH in all samples and comparisons between individuals with and without SCD were performed.RESULTSWhile we had sufficient power to detect a greater than 2-fold increased rate of CH, we found no detectable variation in rate or clone properties between individuals affected by SCD and controls. The rate of CH in individuals with SCD was unaltered by hydroxyurea use.CONCLUSIONSWe did not observe an increased risk for acquiring detectable CH in SCD, at least as measured by whole-genome sequencing. These results should help guide ongoing efforts and further studies 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.FUNDINGNew York Stem Cell Foundation and the NIH.

Full Text

Duke Authors

Cited Authors

  • Liggett, LA; Cato, LD; Weinstock, JS; Zhang, Y; Nouraie, SM; Gladwin, MT; Garrett, ME; Ashley-Koch, A; Telen, MJ; Custer, B; Kelly, S; Dinardo, CL; Sabino, EC; Loureiro, P; Carneiro-Proietti, AB; Maximo, C; NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, ; Reiner, AP; Abecasis, GR; Williams, DA; Natarajan, P; Bick, AG; Sankaran, VG

Published Date

  • February 15, 2022

Published In

Volume / Issue

  • 132 / 4

PubMed ID

  • 34990411

Pubmed Central ID

  • PMC8843701

Electronic International Standard Serial Number (EISSN)

  • 1558-8238

Digital Object Identifier (DOI)

  • 10.1172/JCI156060


  • eng

Conference Location

  • United States