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Targeting Expression of the Leukemogenic PML-RAR alpha Fusion Protein by Lentiviral Vector-Mediated Small Interfering RNA Results in Leukemic Cell Differentiation and Apoptosis

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Author

Summary, in English

Acute promyelocytic leukemia (APL) results from a chromosomal translocation that gives rise to the leukemogenic fusion protein PML-RAR alpha (promyelocytic leukemia-retinoic acid alpha receptor). Differentiation of leukemic cells and complete remission of APL are achieved by treatment of patients with pharmacological doses of all-trans retinoic acid (ATRA), making APL a model disease for differentiation therapy. However, because patients are resistant to further treatment with ATRA on relapse, it is necessary to develop alternative treatment strategies to specifically target APL. We therefore sought to develop a treatment strategy based on lentiviral vector-mediated delivery of small interfering RNA (siRNA) that specifically targets the breakpoint region of PML-RAR alpha. Unlike treatment with ATRA, which resulted in differentiation of leukemic NB4 cells, delivery of siRNA targeting PML-RAR alpha into NB4 cells resulted in both differentiation and apoptosis, consistent with the specific knockdown of PML-RAR alpha. Intraperitoneal injection of NB4 cells transduced with lentiviral vectors delivering PML-RAR alpha-specific siRNA but not control siRNA prevented development of disease in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. Taken together, these results indicate that development of PML-RAR alpha-specific siRNA may represent a promising treatment strategy for ATRA-resistant APL.

Publishing year

2011

Language

English

Pages

1593-1598

Publication/Series

Human Gene Therapy

Volume

22

Issue

12

Document type

Journal article

Publisher

Mary Ann Liebert, Inc.

Topic

  • Medical Genetics

Status

Published

Research group

  • Hematopoietic Stem Cell Development

ISBN/ISSN/Other

  • ISSN: 1043-0342