Transforming growth factor-beta (TGF-beta)-resistant B cells from chronic lymphocytic leukemia patients contain recurrent mutations in the signal sequence of the type I TGF-beta receptor.
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-beta (TGF-beta). Herein, we identified two mutations within the putative signal sequence of TGF-beta type I receptor (TbetaR-I) gene of TGF-beta-resistant B-CLL patients (i.e., a Leu12Gln substitution together with an in-frame single Ala deletion). Although TbetaR-I mutants were expressed to the cell surface and interacted normally with TGF-beta-bound TbetaR-II, their expression significantly reduced gene transcription stimulated by TGF-beta, suggesting a causal relationship in the development of TGF-beta-resistant B-CLL. Screening of additional B-CLL patients solely for the presence of TbetaR-I signal sequence mutations showed that these mutations correlated with and predicted for B-CLL patient insensitivity to TGF-beta. Our results demonstrate that TGF-beta-resistant B-CLL is linked to signal sequence mutations within the TbetaR-I gene, and may eventually be employed as a prognostic indicator in B-CLL.
Schiemann
William P
WP
Department of Pediatrics, Program in Cell Biology, National Jewish Medical and Research Center, Goodman Building, K1011, 1400 Jackson Street, Denver, CO 80206, USA. schiemannwp@njc.org
Rotzer
Diana
D
Pfeifer
Waither M
WM
Levi
Edi
E
Rai
Kanti R
KR
Knaus
Petra
P
Kadin
Marshall E
ME
D001402:B-Lymphocytes / Q000187:drug effects / Q000502:physiology; D001483:Base Sequence; D002478:Cells, Cultured; D019008:Drug Resistance, Neoplasm; D020022:Genetic Predisposition to Disease; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D008969:Molecular Sequence Data; D009154:Mutation; D016133:Polymerase Chain Reaction; D021382:Protein Sorting Signals; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics*; D012680:Sensitivity and Specificity; D016212:Transforming Growth Factor beta / Q000494:pharmacology* / Q000627:therapeutic use
D021382:Protein Sorting Signals; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta