Education and Training:

B.S. Biophysics, Yerevan University, Yerevan, Armenia (1983)

M.Sc. Protein Chemistry, Protein Research Institute, Puschino, Moscow University, Moscow, Russia (1984)

Ph.D. Molecular Biology, Institute of Molecular Biology, Academy of Sciences, Moscow, Russia (1988)

Staff Scientist, Institute of Biochemistry, USSR Academy of Sciences, Yerevan, Armenia (1988-90)

Senior Scientist, Department of Molecular Biology of Aging, NASA, Institute of Biochemistry, Yerevan, Armenia (1990-93)

Senior Fellow, Division of Oncology, Department of Medicine, University of Washington, Seattle, WA (1993-97)

Senior Fellow, Division of General Internal Medicine, Department of Medicine, University of Washington, Seattle, WA (1998)

Current Research Interests
Research is focused on identification of molecular defects and regulation of intracellular events implicated in pathogenesis of inherited severe neutropenia

Research Description
Our research focuses on understanding the molecular events governing cell proliferation, survival and differentiation in severe congenital neutropenia (SCN) and it’s evolution to acute myelogenous leukemia (AML).

Severe congenital neutropenia (SCN) is characterized by a selective decrease in the number of circulating neutrophils associated with recurrent fevers, chronic oropharyngeal inflammation and recurring severe infections. SCN is inherited as autosomal dominant or recessive disease, it’s usually diagnosed in early childhood and may evolve to AML in the second decade of life. Current therapy of SCN with granulocyte colony-stimulating factor (G-CSF) increases the level of circulating neutrophils and reduces frequency of infection-related events. Severe neutropenia in these patients is due to impaired formation and reduced delivery of neutrophils from the bone marrow to the peripheral circulation. Our recent studies demonstrated that accelerated apoptosis of myeloid-committed progenitor cells is the cellular mechanism underlying lack of neutrophils in SCN. We also reported that more than 90% of patients with inherited or acquired SCN harbor heterozygous mutations in the neutrophil elastase (NE) gene. Molecular studies of SCN evolving to AML revealed acquired heterozygous mutations in the granulocyte colony-stimulating factor receptor (G-CSFR) gene implicating this gene product in leukemogenesis in SCN.

Using modern methods of cellular and molecular biology, our ongoing studies are directed towards investigation of 1) diversity and the role of NE and G-CSFR mutations in pathogenesis of SCN and SCN/AML, 2) subcellular localization, substrate specificity, and enzymatic activity of mutant NE, 3) role of mutant NE and G-CSFR in regulation of myeloid differentiation, 4) establishment and characterization of cellular and animal models of SCN/AML which will be useful for development of novel therapeutic strategies for treatment of SCN and prevention of its leukemic evolution.

The molecular and cellular studies of cyclic neutropenia (CN) and related diseases (idiopathic neutropenia, myelokathexis) are ongoing in collaboration with Dr. David Dale. The goal of this line of investigation is to understand the pathogenesis of these disorders, and how different mutations in the same NE gene lead to cyclic hematopoiesis phenotype.

Selected Publications

Aprikyan AA, Kutyavin T, Stein S, Aprikian P, Rodger E, Liles WC, Boxer LA, Dale DC. Cellular and molecular abnormalities in severe congenital neutropenia predisposing to leukemia.  Exp. Hematol. 31:372-81, 2003.

Aprikyan AA, Liles WC, Boxer LA, Dale DC. Mutant elastase in pathogenesis of cyclic and severe congenital neutropenia. J. Pediatr. Hematol Oncol. 24:784-6, 2002.

Aprikyan AA, Liles WC, Rodger E, Jonas M, Chi EY, Dale DC. Impaired survival of bone marrow hematopoietic progenitor cells in cyclic neutropenia. Blood 97:147-53, 2001.

Dale DC, Person RE, Bolyard AA, Aprikyan AG, Bos C, Bonilla MA, Boxer LA, Kannourakis G, Zeidler C, Welte K, Benson KF, Horwitz M.  Mutations in the gene encoding neutrophil elastase in congenital and cyclic neutropenia. Blood 96:2317-22, 2000.

Aprikyan AA, Liles WC, Dale DC. Emerging role of apoptosis in the pathogenesis of severe neutropenia. Curr. Opin. Hematol. 7:131-2, 2000.