RT Journal Article
T1 NUMB inactivation confers resistance to imatinib in chronic myeloid leukemia cells.
A1 Garcia-Alegria, Eva
A1 Lafita-Navarro, M Carmen
A1 Aguado, Rocio
A1 Garcia-Gutierrez, Lucia
A1 Sarnataro, Kyle
A1 Ruiz-Herguido, Cristina
A1 Martin, Francisco
A1 Bigas, Anna
A1 Canelles, Matilde
A1 Leon, Javier
K1 Chronic myeloid leukemia
K1 Imatinib
K1 NUMB
AB Chronic myeloid leukemia (CML) progresses from a chronic to a blastic phase, where the leukemic cells are proliferative and undifferentiated. The CML is nowadays successfully treated with BCR-ABL kinase inhibitors as imatinib and its derivatives. NUMB is an evolutionary well-conserved protein initially described as a functional antagonist of NOTCH function. NUMB is an endocytic protein associated with receptor internalization, involved in multiple cellular functions. It has been reported that MSI2 protein, a NUMB inhibitor, is upregulated in CML blast crisis, whereas NUMB itself is downregulated. This suggest that NUMB plays a role in the malignant progression of CML. Here we have generated K562 cells (derived from CML in blast crisis) constitutively expressing a dominant negative form of NUMB (dnNUMB). We show that dnNUMB expression confers a high proliferative phenotype to the cells. Importantly, dnNUMB triggers a partial resistance to imatinib in these cells, antagonizing the apoptosis mediated by the drug. Interestingly, imatinib resistance is not linked to p53 status or NOTCH signaling, as K562 lack p53 and imatinib resistance is reproduced in the presence of NOTCH inhibitors. Taken together, our data support the hypothesis that NUMB activation could be a new therapeutic target in CML.
PB Elsevier
YR 2016
FD 2016-02-23
LK http://hdl.handle.net/10668/9895
UL http://hdl.handle.net/10668/9895
LA en
NO García-Alegría E, Lafita-Navarro MC, Aguado R, García-Gutiérrez L, Sarnataro K, Ruiz-Herguido C, et al. NUMB inactivation confers resistance to imatinib in chronic myeloid leukemia cells. Cancer Lett. 2016 May 28;375(1):92-99
NO The work was supported by grants SAF2014-53526 (to JL), BFU2007-67476 and BFU2010-21634 (to MC) from Spanish Ministry of Economy and  Competitiveness (MINECO), and RD12/0036/0033 (to JL), RD12/0036/0054 (to AB) and RD12/0019/0006 and PI12/01097 (to FM) from Instituto Carlos III, and grant PI-57069 from CICE, FEDER/Fondo de Cohesion Europeo (FSE) de Andalucía 2007–2013 (to FM). The funding from MINECO and Instituto CarlosIII was co-sponsored by the European Union FEDER program. EGA was supported with a JAE-doc contract form CSIC, MCL-N was supported by the FPU program from MINECO and LG-G. We thank Rosa Blanco for excellent technical advice by the FPI program from MINECO.
DS RISalud
RD Apr 14, 2025