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 Detalle_Publicacion

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.

Otras publicaciones de la misma revista o congreso con autores/as de la Universidad de Cantabria

 Fuente: Cancer Lett. 2016 May 28;375(1):92-9

Editorial: Elsevier Science Ireland

 Año de publicación: 2016

Nº de páginas: 8

Tipo de publicación: Artículo de Revista

 DOI: 10.1016/j.canlet.2016.02.037

ISSN: 0304-3835

Autores/as

EVA GARCIA ALEGRIA

MARIA DEL CARMEN LAFITA NAVARRO

AGUADO, R.

LUCIA GARCIA GUTIERREZ

SARNATARO, KYLE

RUIZ HERGUIDO, C.

MARTÍN, F.

BIGAS, ANNA

CANELLES, M.