Proposed model of the abrogated granulopoiesis in CN patients due to the diminished SLPI levels. In CN patients harboring ELANE or HAX1 mutations, expression of LEF-1 transcription factor is severely downregulated. This resulted in the diminished expression of LEF-1 target genes, including ELANE and C/EBPα. Both decreased ELANE levels and mutated ELANE failed to induce SLPI, which is normally activated by wild-type ELANE. Low SLPI expression causes abrogated G-CSF–triggered phosphorylation of ERK1/2, phosphorylation and activation of LEF-1 transcription factor, c-Myc–triggered proliferation, and activation of cell-cycle genes. Expression of the myeloid-specific target gene of LEF-1, C/EBPα, is diminished and C/EBPα failed to activate the SLPI promoter. NF-κB signaling is also dysregulated. These pathological intracellular events ultimately lead to the defective granulocytic differentiation of hematopoietic cells in CN patients.