Nancy Berliner

Department of Medicine

Chief, Division of Hematology
Brigham and Women's Hospital
75 Francis Street

Lab: Karp 5
Boston, MA 02115
Tel: (617) 732-5840
Fax: (617) 264-5215
Email: nberliner@partners.org

The main focus of the research in my laboratory has been on the dissection of the molecular pathways involved in differentiation of granulocytes.  Main projects in my laboratory include:

Regulation of neutrophil-specific gene expression:  Evidence from study of both normal and leukemic cells suggests that a crucial step in neutrophil maturation occurs in the transition from the promyelocyte to the myelocyte stage.  This transition is marked by a change in the granule content of the developing granulocyte.  The transition to the myelocyte stage is associated with the acquisition of secondary (“specific”) granules.  Secondary granules are a unique marker of commitment to terminal neutrophil maturation. In the early years of this research, we cloned the cDNA and chromosomal genes for the four content proteins of the neutrophil secondary granule, and confirmed their stage and tissue specific regulation at the level of mRNA transcription. Since then, we have made progress in elucidating the shared transcriptional regulatory pathways that direct this coordinate expression, and have characterized the transcription factors mediating positive as well as negative regulation of these genes.

Generation of hematopoietic cell lines: We have developed techniques for isolating factor-dependent cell lines from normal mice and mice with targeted disruption of myeloid transcription factors. These provide interesting models for diseases of neutrophil maturation, including myelodysplastic syndromes and neutrophil secondary granule deficiency

Role of cytokine polymorphisms in the pathophysiology of anemia in the elderly: Although it is clear that anemia is an independent risk factor associated with reduced survival in patients over age 65, the etiology of anemia in at least one third of these patients is unknown, as is the pathogenesis by which it leads to physical decline and death. Our central hypothesis is that in the absence of nutritional deficiency, anemia in the elderly usually reflects a proinflammatory state with an associated anemia of inflammation. We would suggest that HIV induces a frail state similar to that seen in the elderly with a more frequent and earlier anemia that reflects an acceleration of the inflammatory process associated with aging. We have undertaken studies in collaboration with the VA cohort study to test these hypotheses.

References:

• Khanna-Gupta A, Zibello T, Sun H, Lekstrom-Himes J, Berliner N. C/EBPe mediates myeloid differentiation and is regulated by the CCAAT displacement protein (CDP/cut). Proc Natl Acad Sci USA 98: 8000-8005, 2001.
• Khanna-Gupta A, Zibello T, Sun H, Gaines P, Berliner N. Chromatin immunopecipitation studies indicate a role for CCAAT enhancer binding proteins alpha (C/EBPa), epsilon (C/EBPe) and CDP/cut in myeloid maturation-induced lactoferrin gene expression. Blood 101: 3460-3468, 2003.
• Gaines P, Chi J, Berliner N. Heterogeneity of functional response in differentiated myeloid cell lines reveals EPRO cells as a valid model of neutrophil functional activation. J Leuk Biol 77:669-79, 2005.
• Khanna-Gupta A, Hong S, Zibello T, Lee HM, Dahl R, Boxer LA, Berliner N. Growth factor independence 1 (Gfi-1) plays a role in mediating specific granule deficiency (SGD) in a patient lacking a gene inactivating mutation in the C/EBPe gene. Blood. 2007; 109:4181-90.