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Background: Despite remarkable progress in treatment, patient management and increased survival rate, childhood acute lymphoblastic leukemia (ALL) remains a major public health problem. Traditionally white blood cell count (WBC) at diagnosis has been used as a prognostic marker. However, the molecular mechanisms and biological pathways modulating WBC have not been characterized. Here, we investigated whether genomic alterations in childhood ALL patients diagnosed with high (HWBC) and patients diagnosed with low (LWBC) could lead to measurable changes distinguishing the two patient groups and discovery of signaling pathways modulating WBC. Methods:We addressed this knowledge gap by comparing gene expression levels between 99 patients diagnosed with LWBC and 108 patients diagnosed with HWBC. Highly significantly differentially expressed genes resulting from the analysis were subjected to network and pathway analysis using the Ingenuity pathway analysis (IPA) software. Results:We discovered a signature of 289 highly significantly differentially expressed genes distinguishing patients with LWBC from patients with HWBC. We discovered gene regulatory networks containing functionally related genes with overlapping functions. The investigation revealed multiple biological pathways including protein ubiquitination, NRF2-mediated oxidative stress response, FGF, AMPK, CD40, Erythropoietin, JAK/STAT, B cell receptor, STAT3, IL-12, Role of JAK1, JAK2 and TYK2 interferon and P53 signalling pathways dysregulated in response to increased WBC. Conclusion:The investigation revealed a prognostic signature distinguishing patient diagnosed with LWBC from patients diagnosed with HWBC. Additionally, the study revealed multiple signaling pathways modulating WBC, which could serve as therapeutic targets. Further research is recommended to integrate transcriptome data on WBC with information on other prognostic markers.