Combination of KIT gene silencing and tocopherol succinate may offer improved therapeutic approaches for human mastocytosis
Irene Ruano,
Ricardo Gargini,
Marta Izquierdo,
Irene Ruano
Centro de Biología Molecular Severo Ochoa (CSIC), Departamento de Biología Molecular (Universidad Autónoma de Madrid), Cantoblanco, Madrid, Spain
Search for more papers by this authorRicardo Gargini
Centro de Biología Molecular Severo Ochoa (CSIC), Departamento de Biología Molecular (Universidad Autónoma de Madrid), Cantoblanco, Madrid, Spain
Search for more papers by this authorMarta Izquierdo
Centro de Biología Molecular Severo Ochoa (CSIC), Departamento de Biología Molecular (Universidad Autónoma de Madrid), Cantoblanco, Madrid, Spain
Search for more papers by this authorIrene Ruano,
Ricardo Gargini,
Marta Izquierdo,
Irene Ruano
Centro de Biología Molecular Severo Ochoa (CSIC), Departamento de Biología Molecular (Universidad Autónoma de Madrid), Cantoblanco, Madrid, Spain
Search for more papers by this authorRicardo Gargini
Centro de Biología Molecular Severo Ochoa (CSIC), Departamento de Biología Molecular (Universidad Autónoma de Madrid), Cantoblanco, Madrid, Spain
Search for more papers by this authorMarta Izquierdo
Centro de Biología Molecular Severo Ochoa (CSIC), Departamento de Biología Molecular (Universidad Autónoma de Madrid), Cantoblanco, Madrid, Spain
Search for more papers by this authorProfessor Marta Izquierdo, Molecular Biology Department, Centro de Biologia Molecular Severo Ochoa (CSIC), Autonomous University of Madrid, Nicolás Cabrera, 1 UAM Cantoblanco, 28049 Madrid, Spain. E-mail: [email protected]
Summary
Gain-of-function mutations of kit tyrosine kinase receptor are associated with mastocytosis. Two subclones of the HMC1 mast leukaemia cell line were used; both express an identical KIT allele-specific regulatory type mutation (V560G), but differ in that one also expresses an enzymatic site type mutation (D816V) that confers on them resistance to imatinib mesylate tyrosine kinase inhibitor. In both cell lines, proliferation was suppressed and apoptosis induced by the combination of KIT gene silencing and α-tocopherol succinate (α-TOS), a derivate of α-tocopherol, also known as vitamin E. Furthermore, HMC1 cells with decreased kit levels by KIT silencing, failed to form tumours when xenotransplanted into immunocompromised mice and the animals were treated systemically with α-TOS. Targeting kit in the presence of α-TOS represents a new approach against proliferation of human mast leukaemia cell lines.
Supporting Information
Fig S1. Percentage of fragmented DNA in cells transfected with retroviruses carrying the DNA to be transcribed to shRNA against KIT (Tot, Mut) or control empty retrovirus vector (Co) in the absence or presence of α-TOS (15 μmol/l) and/or the general caspase inhibitor, z-VAD-fmk, at a concentration of 25 μmol/l.
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