NUMB inactivation confers resistance to imatinib in chronic myeloid leukemia cells

Autor: Cristina Ruiz-Herguido, M. Carmen Lafita-Navarro, Rocío Aguado, Lucía García-Gutiérrez, Matilde Cañelles, Francisco Martin, Javier León, Eva Garcia-Alegria, Anna Bigas, Kyle Sarnataro
Přispěvatelé: Junta de Andalucía, Consejo Superior de Investigaciones Científicas (España), European Commission, Ministerio de Economía y Competitividad (España), Instituto de Salud Carlos III, Universidad de Cantabria
Rok vydání: 2015
Předmět:
0301 basic medicine
Cancer Research
animal structures
Notch signaling pathway
Fusion Proteins
bcr-abl
Gene Expression
Antineoplastic Agents
Nerve Tissue Proteins
Biology
03 medical and health sciences
0302 clinical medicine
NUMB
Downregulation and upregulation
hemic and lymphatic diseases
Leukemia
Myelogenous
Chronic
BCR-ABL Positive
medicine
Humans
Imatinib (Medicament)
Leucèmia mieloide aguda -- Aspectes genètics
neoplasms
Cell Proliferation
Genes
Dominant
Chronic myeloid leukemia
Myeloid leukemia
Membrane Proteins
Imatinib
030104 developmental biology
Imatinib mesylate
Oncology
Drug Resistance
Neoplasm
030220 oncology & carcinogenesis
Immunology
Cancer research
Imatinib Mesylate
Signal transduction
K562 Cells
hormones
hormone substitutes
and hormone antagonists
K562 cells
medicine.drug
HeLa Cells
Signal Transduction
Zdroj: Digital.CSIC. Repositorio Institucional del CSIC
instname
Cancer Lett. 2016 May 28;375(1):92-9
UCrea Repositorio Abierto de la Universidad de Cantabria
ISSN: 1872-7980
Popis: 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.
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 Carlos III 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.
Databáze: OpenAIRE
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