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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

Ward, Simone V.; Sternsdorf, Thomas and Woods, Niels-Bjarne LU (2011) In Human Gene Therapy 22(12). p.1593-1598
Abstract
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... (More)
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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Human Gene Therapy
volume
22
issue
12
pages
1593 - 1598
publisher
Mary Ann Liebert, Inc.
external identifiers
  • wos:000298343700013
  • scopus:83455206230
ISSN
1043-0342
DOI
10.1089/hum.2011.079
language
English
LU publication?
yes
id
836f28c2-4986-44ae-ba0b-a3497be57493 (old id 2333222)
date added to LUP
2012-02-01 07:38:00
date last changed
2017-01-24 16:26:11
@article{836f28c2-4986-44ae-ba0b-a3497be57493,
  abstract     = {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.},
  author       = {Ward, Simone V. and Sternsdorf, Thomas and Woods, Niels-Bjarne},
  issn         = {1043-0342},
  language     = {eng},
  number       = {12},
  pages        = {1593--1598},
  publisher    = {Mary Ann Liebert, Inc.},
  series       = {Human Gene Therapy},
  title        = {Targeting Expression of the Leukemogenic PML-RAR alpha Fusion Protein by Lentiviral Vector-Mediated Small Interfering RNA Results in Leukemic Cell Differentiation and Apoptosis},
  url          = {http://dx.doi.org/10.1089/hum.2011.079},
  volume       = {22},
  year         = {2011},
}