Abstract
B cell chronic lymphocytic leukemia (B-CLL) is the most common leukemia in western societies, and is currently incurable. B cells of some B-CLL patients are resistant to the anti-proliferative effects of transforming growth factor-β (TGF-β). Herein, we identified two mutations within the putative signal sequence of TGF-β type I receptor (TβR-I) gene of TGF-β-resistant B-CLL patients (i.e., a Leu12Gln substitution together with an in-frame single Ala deletion). Although TβR-I mutants were expressed to the cell surface and interacted normally with TGF-β-bound TβR-II, their expression significantly reduced gene transcription stimulated by TGF-β, suggesting a causal relationship in the development of TGF-β-resistant B-CLL. Screening of additional B-CLL patients solely for the presence of TβR-I signal sequence mutations showed that these mutations correlated with and predicted for B-CLL patient insensitivity to TGF-β. Our results demonstrate that TGF-β-resistant B-CLL is linked to signal sequence mutations within the TβR-I gene, and may eventually be employed as a prognostic indicator in B-CLL.
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