The tyrosine kinase anaplastic lymphoma kinase (ALK) is normally found in neural cells, but chromosomal translocations involving ALK and the nucleophosmin gene, NPM1, occur in T cell lymphomas (NPM1-ALK+ TCLs). Zhang et al. investigated a role for signal transducer and activator of transcription 5A (STAT5A) in the transformation of NPM1-ALK+ TCLs. Western blotting showed the presence of STAT5A in T cells from healthy donors, but not in NPM1-ALK+ TCLs and T cell lines. STAT5A mRNA was not detectable in NPM1-ALK+ T cell lines as measured by reverse transcription polymerase chain reaction (RT-PCR) assays. DNA sequencing revealed the methylation of almost all of the CpG sites in the STAT5A promoter of NPM1-ALK+ TCL cells obtained from patients, but no methylation in T cells from healthy donors. DNA methylation of gene promoters inhibits their transcription. Chromatin immunoprecipitation (ChIP) assays showed that SP1, an activator of STAT5A transcription, could not bind to the methylated STAT5A promoter in NPM1-ALK+ T cells. Treatment of NPM1-ALK+ T cells with the DNA methyltransferase inhibitor 5′-aza-2′-deoxycytidine (5′-aza) led to a time-dependent increase in the expression of STAT5A and the abundance of STAT5A protein. This was associated with a gradual decrease in the abundance of NPM1-ALK protein. Electrophoretic mobility shift assays showed that STAT5A bound directly to the enhancer region of NPM1-ALK. Transfection of an NPM1-ALK+ T cell line with a small inhibitor RNA specific for NPM1-ALK resulted in the induction of STAT5A expression. Finally, treatment of NPM1-ALK+ T cells with 5′-aza suppressed their growth in vitro. These results suggest that STAT5A acts as a tumor suppressor and that inhibiting ALK activity, which would prevent the silencing of STAT5A, might be therapeutically beneficial.
Q. Zhang, H. Y. Wang, X. Liu, M. A. Wasik, STAT5A is epigenetically silenced by the tyrosine kinase NPM1-ALK and acts as a tumor suppressor by reciprocally inhibiting NPM1-ALK expression. Nat. Med. 13, 1341-1348 (2007). [PubMed]