Skokowa J, Cario G, Uenalan M, et al. LEF-1 is crucial for neutrophil granulocytopoiesis and its expression is severely reduced in congenital neutropenia. Nat Med 2006;12:1191-7.

Congenital neutropenia (CN) is associated with mutation of a number of genes including elastase, G-CSF receptor, GFI-1, and WASP; however, in many cases the underlying defect is not established. In this manuscript, the focus shifts to analysis of LEF-1, whose role as a transcription factor that is important in lymphocyte proliferation and differentiation is well established. The authors compare mRNA expression patterns in CD33+ cells from patients with congenital neutropenia to those from normal donors, as well as those with neutropenia from other causes, and found that there was a marked reduction in expression of LEF-1 in cells from patients with CN, but not those with other forms of neutropenia or normal neutrophils. Although half of the 13 patients with CN in this study had mutations in the ELA2 gene, all had reduced levels of LEF-1 and maturation arrest. The differences in expression level were evident beyond the blast stage and were most dramatic in the promyelocyte. Expression of LEF-1 in progenitor cells from patients with CN enables differentiation. The investigators propose that regulation occurs through the ß-catenin-independent action of LEF-1 and is likely due to a balance between proliferative and apoptotic factors.

The work here not only characterizes factors that may be important in cyclic neutropenia, but also establishes a role for the transcription factor LEF-1 in myelopoiesis. An earlier report by Li et al.1  demonstrated that LEF-1 was expressed in bone marrow cells and myeloid cell lines and identified a LEF-1 binding domain that was mutated in two patients with severe chronic neutropenia. Of interest is that LEF-1 binding to the promoter is enhanced by the mutation that was uncovered in both of the patients described and results in increased elastase production. In contrast, in the patients studied in this manuscript, diminished LEF-1 expression — and thus activity — are thought to be critical for the maturation arrest, diminished proliferation, and decreased cell survival that is observed in these patients. Here, the investigators used two techniques to confirm that LEF-1 expression was necessary for maturation of myeloid precursors — expression in progenitors from patients with CN enabled differentiation; and disruption of its expression by small hair-pin RNAs resulting in maturation arrest, diminished proliferation, and decreased cell survival. In probing for mechanisms, LEF-1 overexpression enhances CEBP expression independently of G-CSF that normally regulates its expression. Of note is that G-CSF had little effect on LEF-1 levels under “physiologic” concentrations but is hypothesized to upregulate its expression at pharmacologic doses. This manuscript characterizes a group of patients with congenital neutropenia that have diminished LEF-1 expression. It remains to be seen whether this finding is consistent among a larger cohort of patients. Nonetheless, the data presented here demonstrate that its expression level plays a role in myeloid cell differentiation and implicate it in neutropenia. Since analysis of the promoter region LEF-1 has not identified a potential mutation site, the next step will be to determine the post-transcriptional regulatory step that may be altered in these patients.

1.
Li F-Q, Person RE, Takemaru K-I et al. Lymphoid enhancer factor-1 links two hereditary leukemia syndromes through core-binding factor regulation of ELAJ Biol Chem 2004;279:2873–

Competing Interests

Dr. Petruzzelli indicated no relevant conflicts of interest.