title: NUMB inactivation confers resistance to imatinib in chronic myeloid leukemia cells.
abstract: 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.
authors.affiliation: Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), CSIC-Universidad de Cantabria and Dpto. de Biología Molecular, Universidad de Cantabria, Santander, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: García-Alegría
authors.affiliation: Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), CSIC-Universidad de Cantabria and Dpto. de Biología Molecular, Universidad de Cantabria, Santander, Spain.
authors.forename: M Carmen
authors.initials: MC
authors.lastname: Lafita-Navarro
authors.affiliation: Instituto de Parasitología y Biomedicina, CSIC, P. T. Ciencias de la Salud, Granada, Spain.
authors.forename: Rocío
authors.initials: R
authors.lastname: Aguado
authors.affiliation: Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), CSIC-Universidad de Cantabria and Dpto. de Biología Molecular, Universidad de Cantabria, Santander, Spain.
authors.forename: Lucia
authors.initials: L
authors.lastname: García-Gutiérrez
authors.affiliation: Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), CSIC-Universidad de Cantabria and Dpto. de Biología Molecular, Universidad de Cantabria, Santander, Spain.
authors.forename: Kyle
authors.initials: K
authors.lastname: Sarnataro
authors.affiliation: Stem Cells and Cancer Group. IMIM, Barcelona, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Ruiz-Herguido
authors.affiliation: Genyo, P.T. Ciencias de la Salud, Granada, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Martín
authors.affiliation: Stem Cells and Cancer Group. IMIM, Barcelona, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Bigas
authors.affiliation: Instituto de Parasitología y Biomedicina, CSIC, P. T. Ciencias de la Salud, Granada, Spain. Electronic address: mcanelles@ipb.csic.es.
authors.forename: Matilde
authors.initials: M
authors.lastname: Canelles
authors.affiliation: Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), CSIC-Universidad de Cantabria and Dpto. de Biología Molecular, Universidad de Cantabria, Santander, Spain. Electronic address: javier.leon@unican.es.
authors.forename: Javier
authors.initials: J
authors.lastname: León
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism; D015870:Gene Expression; D005799:Genes, Dominant; D006367:HeLa Cells; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology*; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000970:Antineoplastic Agents; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C113026:NUMB protein, human; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl
keywords: Chronic myeloid leukemia; Imatinib; NUMB