Targeting Expression of the Leukemogenic PML-RAR alpha Fusion Protein by Lentiviral Vector-Mediated Small Interfering RNA Results in Leukemic Cell Differentiation and Apoptosis
Författare
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.
Avdelning/ar
Publiceringsår
2011
Språk
Engelska
Sidor
1593-1598
Publikation/Tidskrift/Serie
Human Gene Therapy
Volym
22
Issue
12
Dokumenttyp
Artikel i tidskrift
Förlag
Mary Ann Liebert, Inc.
Ämne
- Medical Genetics
Status
Published
Forskningsgrupp
- Hematopoietic Stem Cell Development
ISBN/ISSN/Övrigt
- ISSN: 1043-0342