NUMB inactivation confers resistance to imatinib in chronic myeloid leukemia cells

Eva García-Alegría, M. Carmen Lafita-Navarro, Rocío Aguado, Lucia García-Gutiérrez, Kyle Sarnataro, Cristina Ruiz-Herguido, Francisco Martín, Anna Bigas, Matilde Canelles, Javier León

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)92-99
Number of pages8
JournalCancer Letters
Volume375
Issue number1
DOIs
StatePublished - May 28 2016
Externally publishedYes

Keywords

  • Chronic myeloid leukemia
  • Imatinib
  • NUMB

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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