Defective expression of the T-cell receptor-CD3 zeta chain in T-cell acute lymphoblastic leukaemia.
This study analysed the T-cell receptor (TCR)-CD3 zeta complex and the signal transduction apparatus of T-acute lymphoblastic leukaemia (T-ALL) blasts, and investigated the function of the ubiquitin-proteasome system. In all nine T-ALL samples studied, the leukaemic cells showed a marked reduction in the expression of the zeta chain, while a variety of tyrosine kinases (p56lck, ZAP70 and SYK) were normally present. There was no expression of the FcepsilonRIgamma chain. To confirm that this aberration was specific to immature T-ALL blasts, we investigated two patients with lymphoproliferative disorders of granular lymphocytes (LDGL), characterized by the expansion of mature T lymphocytes and found normal zeta chain expression. The reduction of the zeta chain protein was not reversible after 72 h stimulation with the anti-CD3 monoclonal antibody and interleukin 2, either alone or in combination. Northern blot analysis indicated that the reduced protein expression did not correspond to a defect at the mRNA level, nor were mutations in the coding region of the zeta chain found. We, therefore, hypothesized that the observed reduction of protein expression in T-ALL blasts could be secondary to an increased degradation at the proteasome level. Following selective inhibition of the proteasome, a marked increase of the zeta chain expression was observed. Moreover, an increase in the surface expression of CD3 was also documented. Taken together, these results indicate that the expression of the zeta subunit of the TCR-CD3 complex is consistently reduced in T-ALL blasts and that degradation of the protein is mediated by the proteasome system.
Torelli
Giovanni F
GF
Department of Cellular Biotechnologies and Haematology, University of Rome La Sapienza, Italy.
Paolini
Rossella
R
Tatarelli
Caterina
C
Soriani
Alessandra
A
Vitale
Antonella
A
Guarini
Anna
A
Santoni
Angela
A
Foa
Robin
R
D000328:Adult; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression; D006801:Humans; D018960:Hyaluronan Receptors / Q000276:immunology; D007142:Immunoglobulin gamma-Chains / Q000235:genetics*; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000276:immunology*; D008163:Luminescent Measurements; D009842:Oligopeptides / Q000494:pharmacology; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D025801:Ubiquitin / Q000378:metabolism
D004791:Enzyme Inhibitors; D018960:Hyaluronan Receptors; D007142:Immunoglobulin gamma-Chains; D009842:Oligopeptides; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D025801:Ubiquitin; C078846:epoxomicin