LEF-1 is crucial for neutrophil granulocytopoiesis and its expression is severely reduced in congenital neutropenia

Julia Skokowa¹, Gunnar Cario^1, 5, 6, Murat Uenalan^1, 6, Axel Schambach^1, 2, Manuela Germeshausen¹, Karin Battmer², Cornelia Zeidler¹, Ulrich Lehmann³, Matthias Eder², Christopher Baum², Rudolf Grosschedl⁴, Martin Stanulla¹, Michaela Scherr² & Karl Welte¹

¹  Departments of Pediatric Hematology and Oncology Carl-Neuberg-Str. 1, 30625 Hannover, Germany.

²  Hematology, Hemostaseology and Oncology Carl-Neuberg-Str. 1, 30625 Hannover, Germany.

³  Pathology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.

⁴  Max Planck Institute of Immunobiology, Department of Cellular and Molecular Immunology, 79108 Freiburg, Germany.

⁵  Present address: Department of Pediatrics, University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany.

⁶  These authors contributed equally to this work.

We demonstrate here that lymphoid enhancer-binding factor 1 (LEF-1) mediates the proliferation, survival and differentiation of granulocyte progenitor cells. We initially documented the importance of this transcription factor in the bone marrow of individuals with severe congenital neutropenia (CN) with a 'differentiation block' at the promyelocytic stage of myelopoiesis¹. LEF-1 expression was greatly reduced or even absent in CN arrested promyelocytes, resulting in defective expression of the LEF-1 target genes CCND1, MYC and BIRC5, encoding cyclin D1 (ref. 2), c-Myc ³ and survivin⁴, respectively. In contrast, healthy individuals showed highest LEF-1 expression in promyelocytes. Reconstitution of LEF-1 in early hematopoietic progenitors of two individuals with CN corrected the defective myelopoiesis and resulted in the differentiation of these progenitors into mature granulocytes. Repression of endogenous LEF-1 by specific short hairpin RNA inhibited proliferation and induced apoptosis of CD34⁺ progenitors from healthy individuals and of cells from two myeloid lines (HL-60 and K562). C/EBP, a key transcription factor in granulopoiesis^{5, 6}, was directly regulated by LEF-1. These observations indicate that LEF-1 is an instructive factor regulating neutrophilic granulopoiesis whose absence plays a critical role in the defective maturation program of myeloid progenitors in individuals with CN.

NOTE: In the version of this article initially published, the DOI was incorrect. The correct DOI is 10.1038/nm1474. The error has been corrected in the HTML and PDF versions of the article.

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