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Introduction Hematopoietic stem cell transplantation (HSCT) is the essential and often the only curative therapeutic option in high risk and relapsed pediatric acute lymphoblastic leukemia (ALL). Methods The objective of the study was to investigate whole-genome expression in children with high risk or relapsed ALL referred for HSCT. Gene expression was assessed in 18 children with ALL referred for HSCT (10 high risk, 8 relapsed; median age of 9.4 years) and in a control group of 38 obese children (median age of 14.1 years). Whole-genome expression was assessed in leukocytes using GeneChip® HumanGene 1.0 ST microarray. Results The analysis of genomic profiles revealed a significantly lower expression of 21 genes with a defined function, involved in immunoglobulin production, lymphocyte function, or regulation of DNA processing in ALL patients referred for HSCT compared with the control group. Conclusion Genome expression of patients with ALL in remission referred to HSCT revealed deep immunosuppression of both B-cell and T-cell lineages, which may increase the probability of donor cell engraftment.