We report on a series of sequential events leading to long-term survival and cure of pediatric X-linked chronic
granulomatous disease (X-CGD) patients after gamma-retroviral gene therapy (GT) and rescue HSCT. Due to therapyrefractory
life-threatening infections requiring hematopoietic stem cell transplantation (HSCT) but absence of HLAidentical
donors, we treated 2 boys with X-CGD by GT. Following GT both children completely resolved invasive Aspergillus
nidulans infections. However, one child developed dual insertional activation of ecotropic viral integration site 1
(EVI1) and signal transducer and activator of transcription 3 (STAT3) genes, leading to myelodysplastic syndrome (MDS)
with monosomy 7. Despite resistance to mismatched allo-HSCT with standard myeloablative conditioning, secondary intensified
rescue allo-HSCT resulted in 100 % donor chimerism and disappearance of MDS. The other child did not develop
MDS despite expansion of a clone with a single insertion in the myelodysplasia syndrome 1 (MDS1) gene and was
cured by early standard allo-HSCT. The slowly developing dominance of clones harboring integrations in MDS1-EVI1
may guide clinical intervention strategies, i.e. early rescue allo-HSCT, prior to malignant transformation. GT was essential
for both children to survive and to clear therapy-refractory infections, and future GT with safer lentiviral self-inactivated
(SIN) vectors may offer a therapeutic alternative for X-CGD patients suffering from life-threatening infections and lacking
HLA-identical HSC donors.
Keywords: Allo-HSCT, CGD, EVI1, Gene therapy, Primary immunodeficiency, Retroviral vector, STAT3, Transactivation.
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