Inhibition of T-cell acute lymphoblastic leukemia proliferation in vivo by re-expression of the p16INK4a tumor suppressor gene.
T-cell acute lymphoblastic leukemia (T-ALL) is characterized by the presence of differentiation-inhibited pro- and pre-T-cell blasts. The p16INK4a tumor suppressor gene has been shown to be frequently deleted in human T-ALL cases. Deletion of p16INK4a may be associated with poor prognosis and relapse of the disease. Radiation-induced murine T-ALL in C57B1/6 mice shares pathogenetic and molecular characteristics with the human disease. We used the murine disease as a model to study the status of the INK4/ARF gene locus and to examine the effect of p16INK4a-re-expression in T-ALL cells on their leukemic potential in vivo. In 9 of 17 radiation-induced murine T-ALL cell lines, the p16INK4a protein was not expressed as determined by immunoblotting. Southern blot analysis revealed homozygous deletions of the p16INK4a gene locus in three of the nine lines, along with the genes encoding p15INK4b and p19ARF. Transduction of p16INK4a-negative T-ALL lines with retrovirus encoding p16INK4a significantly inhibited their in vitro proliferation by inducing G1-arrest. Importantly, re-expression of p16INK4a in p16INK4a-negative T-ALL cells obliterated the induction of lethal disseminated leukemia in syngeneic mice. This is the first demonstration that re-establishment of p16INK4a expression is critical for in vivo growth regulation of T-ALL cells.
Department of Biology and Cancer Center, University of California, San Diego, La Jolla 92093-0063, USA.
K
K
Schoppmeyer
P S
PS
Norris
M
M
Haas
D016475:3T3 Cells; D000818:Animals; D015139:Blotting, Southern; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000235:genetics; D002453:Cell Cycle / Q000235:genetics; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D018450:Disease Progression; D017353:Gene Deletion; D018014:Gene Transfer Techniques; D006801:Humans; D015151:Immunoblotting; D007953:Leukemia, Radiation-Induced / Q000276:immunology / Q000628:therapy; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000276:immunology* / Q000628:therapy*; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011233:Precipitin Tests; D014176:Protein Biosynthesis; D016160:Retinoblastoma Protein / Q000096:biosynthesis; D012190:Retroviridae / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000378:metabolism; D013997:Time Factors; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured; D025803:Tumor Suppressor Protein p14ARF; D025521:Tumor Suppressor Proteins
C493966:CDKN2B protein, human; D002352:Carrier Proteins; C493968:Cdkn2b protein, mouse; D018797:Cell Cycle Proteins; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D016160:Retinoblastoma Protein; D025803:Tumor Suppressor Protein p14ARF; D025521:Tumor Suppressor Proteins