Pre T-cell receptor alpha (pTalpha) expression patterns and functional analysis in human T-cell lymphoblastic leukemia.

BACKGROUND

The pTalpha/preTCR regulates the beta-selection, a crucial T-cell developmental checkpoint, providing a most potent survival advantage to thymocytes mediated by the src-kinase p56(Lck).

METHODS

To define the relevance of pTalpha in human T-cell lymphoblastic leukemia (T-ALL), we analyzed in T-ALL cell lines (n=14) pTalpha and p56(Lck) mRNA and protein expression as also the tyrosine-phosphorylation. The p56(Lck) specific src-protein-tyrosine kinase inhibitor (PTK-I) PP1 was used in growth inhibition assays. IC(50) value determination, cell cycle- and apoptosis analyses were performed in T-ALL-, non-T-ALL- and murine transgenic cell lines.

RESULTS

pTalpha expression patterns were markedly different in T-ALL cell lines as compared to those reported for normal lymphoid counterparts. PP1 induced in 6/11 T-ALL cell lines a survival disadvantage resulting from a cell cycle arrest in the G(1/0) phase in thymic lymphoblastic cells and apoptosis induction in the immature cell line HSB-2, respectively. PP1 sensitive cell lines expressed the target protein p56(Lck) and showed a corresponding P-Tyr signal.

CONCLUSION

Sensitivity of thymic T-ALLs to PP1 clearly underlines the impact of pTalpha mediated proliferation in this leukemic sub-type. In addition, p56(Lck) represents also independently of pTalpha a promising therapeutical target for the src-kinase inhibitors in neoplastic lymphoid diseases.