Pleiotropic expression of heterologous cytokine/receptor genes in HTLV-1 associated diseases: candidate TRS for chimeric gene therapy.
DNA motifs that encode for specific transcriptional regulatory sequences (TRS) when engineered adjacent to the structural protein coding domain of a suicide enzyme can provide cell-lineage specific protein expression. The disparate up-regulation of several genes in adult T-cell leukemia (ATL) versus HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP), seropositive carriers (SPC) and uninfected normals may reflect events at the molecular level related to leukemogenesis or to processes maintaining the heme-oncologic phenotype. Further, the genetic transduction of cytokine and receptor genes uniquely associated with ATL may provide targets for the development of leukemia-specific gene therapies aimed at exploiting differences in the production of certain growth factors and growth factor receptors. Comparisons of the transcriptional and translational levels of interleukin-2 receptor alpha chain (IL-2R alpha), transforming growth factor-beta 1 (TGF-beta 1) and intracellular adhesion molecule-1 (ICAM-1) in ATL, HAM/TSP, and SPC and in several control populations revealed selectively up-regulated expression in ATL. We evaluated the feasibility of using lymphoid-specific TRS to activate herpes simplex virus thymidine kinase (HSVtk) to achieve selective cytotoxicity in leukemias expressing terminal deoxynucleotidyl transferase (TdT). Selective and efficient leukemic cell killing was produced and suggests that similar chimeric gene constructs containing TRS elements for IL-2R alpha, TGF-beta 1, or ICAM-1 may prove useful in designing gene therapies to treat ATL.
Greenberg
S J
SJ
Department of Neurology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
Choi
U
U
Overturf
P M
PM
Glenister
N
N
Robinson
T A
TA
Lis
A
A
Hohmann
P
P
Goldman
B D
BD
Oseroff
A R
AR
Plunkett
R J
RJ
D000328:Adult; D002353:Carrier State / Q000628:therapy; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D007378:Interleukins / Q000096:biosynthesis; D015458:Leukemia, T-Cell / Q000628:therapy*; D015493:Paraparesis, Tropical Spastic / Q000628:therapy*; D015202:Protein Engineering; D018121:Receptors, Cytokine / Q000096:biosynthesis* / Q000235:genetics; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D012045:Regulatory Sequences, Nucleic Acid; D018139:Simplexvirus / Q000235:genetics; D013937:Thymidine Kinase / Q000096:biosynthesis / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000096:biosynthesis
D016207:Cytokines; D007378:Interleukins; D018121:Receptors, Cytokine; D015375:Receptors, Interleukin-2; D016212:Transforming Growth Factor beta; D018799:Intercellular Adhesion Molecule-1; D013937:Thymidine Kinase