Engraftment of hematopoietic stems cells (HSCs) is a potentially life-saving treatment therapy for various conditions including genetic blood cell diseases. In particular, the use of allogeneic HSCs to treat genetic blood cell diseases has become a clinical standard: HSCs can be modified ex vivo and transferred back to the recipient to produce functional, terminally-differentiated cells. There is a medical need for methods for assessing the exhaustion of HSCs for optimizing their therapeutic use, in particular in the context of gene therapy. The inventors performed a clinical trial of lentivirus-based gene therapy for the treatment of X-linked chronic granulomatous disease. Two patients showed stable engraftment and clinical benefits, whereas the other two progressively lost gene-corrected cells. Single-cell transcriptomic analysis revealed a significantly lower frequency of the most immature hematopoietic stem cell (HSC) in CGD patients, more pronounced in patients with defective engraftment. The two patients with defective engraftment presented a profound change in HSC status, a high interferon score, and elevated myeloid progenitor counts. The inventors used elastic-net logistic regression to identify a set of interferon genes and transcription factors that predicted the failure of HSC engraftment. They identified a set of 51 interferon genes and transcription factors that were upregulated specifically in P2 and P5 (including IFI44L, STAT2, IRF9, MX1, SAMD9L, and CEBPB) and that appeared to be predictive of defective HSC engraftment. Accordingly, the identified biomarkers can be very suitable for assessing the exhaustion of hematopoietic stems cells.