NIH Principal Investigator: Andrew Aprikyan, Ph.D. CONFIDENTIAL Abstract Myelokathexis is a rare congenital autosomal dominant disorder characterized by severe chronic neutropenia or leukopenia. The patients have extremely low levels of leukocytes, particularly 9 mature neutrophils in peripheral circulation ranging from 0 to 0.5x10 /L. The characteristic feature of myelokathexis is a presence of bone marrow mature neutrophils with nuclear lobs connected with thin filaments. The patients experience recurrent infections including otitis media and otitis externa, HPV, gingivitis, and severe cutaneous and sinopulmonary infections. In some but not all patients, there is an association of Warts, Hypogammaglobulinemia, and recurrent bronchopulmonary Infections with Myelokathexis (W.H.I.M. syndrome). Myelokathexis patients may evolve to develop fatal B-cell lymphoma, however, no early death related to infections in these patients was reported which is probably due to mobilization of mature marrow neutrophils during infection episodes. Mutations in the CXCR4 gene have been identified in most of the patients with myelokathexis. We cloned the mutant gene products and expressed them in human myeloid progenitor cells. We propose to establish a model of myelokathexis based on tet- regulated expression of mutant CXCR4 in order to further dissect the molecular events mediating development of myelokathexis. We will also test this model in vivo in NOD-SCID mice and will determine the efficacy of identified inhibitors in vivo. These studies will pave important foundation necessary for initiating of clinical trials in patients with myelokathexis. NIH Principal Investigator: Andrew Aprikyan, Ph.D. CONFIDENTIAL Narrative We and others reported premature cell death and identified gene mutations in patients with myelokathexis who suffer from recurring infections [1,2]. These patients may evolve to develop fatal B- cell lymphoma [3]. We propose to establish a cellular model of this disease and test it in vivo in mice. We will use this model to examine the efficacy of identified compounds, which appear to block the abnormalities caused by this mutant gene and restore the normal phenotype. We will study the efficacy of this drug and its analogs in the cellular and animal models of this disease prior to initiating clinical trials in patients.