RT Journal Article
T1 Identification of tipifarnib sensitivity biomarkers in T-cell acute lymphoblastic leukemia and T-cell lymphoma.
A1 Alonso-Alonso, Ruth
A1 Mondéjar, Rufino
A1 Martínez, Nerea
A1 García-Diaz, Nuria
A1 Pérez, Cristina
A1 Merino, David
A1 Rodríguez, Marta
A1 Esteve-Codina, Anna
A1 Fuste, Berta
A1 Gut, Marta
A1 Burrows, Francis
A1 Scholz, Catherine
A1 Vaqué, Jose Pedro
A1 Gualberto, Antonio
A1 Piris, Miguel Ángel
AB Patients diagnosed with T-cell leukemias and T-cell lymphomas (TCLs) still have a poor prognosis and an inadequate response to current therapies, highlighting the need for targeted treatments. We have analyzed the potential therapeutic value of the farnesyltransferase inhibitor, tipifarnib, in 25 TCL cell lines through the identification of genomic and/or immunohistochemical markers of tipifarnib sensitivity. More than half of the cell lines (60%) were considered to be sensitive. Tipifarnib reduced cell viability in these T-cell leukemia and TCL cell lines, induced apoptosis and modified the cell cycle. A mutational study showed TP53, NOTCH1 and DNMT3 to be mutated in 84.6%, 69.2% and 30.0% of sensitive cell lines, and in 62.5%, 0% and 0% of resistant cell lines, respectively. An immunohistochemistry study showed that p-ERK and RelB were associated as potential biomarkers of tipifarnib sensitivity and resistance, respectively. Data from RNA-seq show that tipifarnib at IC50 after 72 h downregulated a great variety of pathways, including those controlling cell cycle, metabolism, and ribosomal and mitochondrial activity. This study establishes tipifarnib as a potential therapeutic option in T-cell leukemia and TCL. The mutational state of NOTCH1, p-ERK and RelB could serve as potential biomarkers of tipifarnib sensitivity and resistance.
YR 2020
FD 2020-04-21
LK http://hdl.handle.net/10668/15408
UL http://hdl.handle.net/10668/15408
LA en
DS RISalud
RD Apr 19, 2025