Hematology 2000
© 2000 The American Society of Hematology
Inherited Neutrophil Disorders
Molecular Basis and New Therapies
Mary C. Dinauer, (Chair),
Julie A. Lekstrom-Himes and
David C. Dale
Abstract
Recent advances in our understanding of the molecular basis of inherited
neutrophil disorders and complementary studies in transgenic mouse models have
provided new insights into the normal mechanisms regulating myelopoiesis and
the functional responses of mature neutrophils. Neutrophil specific granule
deficiency is a rare disorder of neutrophil function characterized by a lack
of neutrophil secondary granule proteins and associated with recurrent
bacterial infections. The CCAAT/enhancer binding protein (C/EBP) 
, a
leucine zipper transcription factor expressed primarily in myeloid cells, and
C/EBP-deficient mice generated by gene targeting lack specific granules
and have impaired host defense are discussed by Dr. Lekstrom-Himes in Section
I. The similarity between these phenotypes led to the identification of a loss
of function mutation in the C/EBP gene in a subset of patients with
specific granule deficiency. Dr. Dale reviews the clinical features and
management of congenital neutropenia and cyclic hematopoiesis in Section II.
Inherited mutations in the neutrophil elastase gene have recently been
identified in both disorders. Specific mutations identified in cyclic and
congenital neutropenia are described along with possible mechanisms for
regulation of hematopoiesis by neutrophil elastase. In Section III, Dr.
Dinauer reviews the molecular genetics of chronic granulomatous disease and
studies in knockout mouse models. This work has revealed important features of
the regulation of the respiratory burst oxidase and its role in host defense
and inflammation. Results from preclinical studies and phase 1 clinical trials
for gene therapy for CGD are summarized, in addition to alternative approaches
using allogeneic bone marrow transplantation with nonmyeloablative
conditioning.
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Copyright © 2000 by the American Society of Hematology.
