The mechanism of dysregulated myeloid differentiation of hematopoietic progenitors in patients with CN. The relative levels of PU.1 and C/EBPα in granulocytic-macrophage progenitors have been suggested to regulate monocyte versus neutrophil cell fate choice. LEF-1 transcription factor could be responsible for the “fine-tuning” of C/EBPα versus PU.1 levels in myeloid cells to induce granulocytic differentiation. LEF-1 transcription factor is absent in myeloid progenitor cells from patients with CN irrespective to mutation status. Therefore, the myelopoietic maturation program in these patients is sharply shifted toward monocytopoiesis. A lack of LEF-1 leads to a severely abrogated C/EBPα and ELA2 expression as well as to elevated PU.1 levels. This misbalanced expression of C/EBPα, ELA2, and PU.1 in hematopoietic cells from patients with CN causes severely diminished granulopoiesis with enhanced monocytic differentiation. In addition, abrogated ELA2 and NE levels cause pathologically high CXCR4 expression on hematopoietic cells of patients with CN, which could cause a defective G-CSF–triggered stem cell mobilization.