Abnormal expression of TGF-beta type II receptor isoforms contributes to acute myeloid leukemia

Altered transforming growth factor-beta (TGF-beta) signaling has been implicated in the pathogenesis of leukemia. Although TGF-beta type II receptor (T beta RII) isoforms have been isolated from human leukemia cells, their expression patterns and functions of these variants are unclear. In this study, we determined that two T beta RII isoforms (T beta RII and T beta RII-B) are abnormally expressed in leukemic cells, as compared to normal hematopoietic cells. T beta RII-B, but not T beta RII, was found to promote cell cycle arrest, apoptosis, and differentiation of leukemic cells. T beta RII-B also enhanced TGF-beta 1 binding and downstream signaling and reduced tumorigenicity in vivo. By contrast, T beta RII blocked all-trans retinoic acid-induced differentiation through inhibition of T beta RII-B. Overall survival was significantly lower in acute myeloid leukemia (AML) patients with high compared to low T beta RII expression. Thus, whereas T beta RII-B is a potent inducer of cell cycle arrest, apoptosis, and differentiation, higher T beta RII expression correlates with poor clinical prognosis in AML.