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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.

 Fuente: Cancer Letters, 2016, 375(1), 92-99

 Publisher: Elsevier Science Ireland

 Year of publication: 2016

 No. of pages: 8

 Publication type: Article

 DOI: 10.1016/j.canlet.2016.02.037

 ISSN: 0304-3835

 Publication Url: https://doi.org/10.1016/j.canlet.2016.02.037

Authorship

EVA GARCIA ALEGRIA

MARIA DEL CARMEN LAFITA NAVARRO

AGUADO, R.

LUCIA GARCIA GUTIERREZ

SARNATARO, KYLE

RUIZ HERGUIDO, C.

MARTÍN, F.

BIGAS, ANNA

CANELLES, M.