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NUMB inactivation confers resistance to imatinib in chronic myeloid leukemia cells.NUMB inactivation confers resistance to imatinib in chronic myeloid leukemia cells.Garcia-Alegría, E., Lafita-Navarro, M.C., Aguado, R., Garcia-Gutierrez, L., Sarnataro, K., Ruiz-Herguido, C., Martín, F., Bigas, A., Canelles, M., and León J.* 2016-05-27T22:00:00Z<p style="text-align:justify;">​<span class="ms-rteThemeFontFace-1 ms-rteFontSize-2"><strong>Abstract</strong></span></p><p style="text-align:justify;"><span class="ms-rteThemeForeColor-2-5 ms-rteFontSize-2">Chronic </span><a href="" title="Learn more about Myeloid"><span class="ms-rteThemeForeColor-2-5 ms-rteFontSize-2">myeloid</span></a><span class="ms-rteThemeForeColor-2-5 ms-rteFontSize-2"> 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 </span><a href="" title="Learn more about Phosphotransferase Inhibitor"><span class="ms-rteThemeForeColor-2-5 ms-rteFontSize-2">kinase inhibitors</span></a><span class="ms-rteThemeForeColor-2-5 ms-rteFontSize-2"> as </span><a href="" title="Learn more about Imatinib"><span class="ms-rteThemeForeColor-2-5 ms-rteFontSize-2">imatinib</span></a><span class="ms-rteThemeForeColor-2-5 ms-rteFontSize-2"> and its derivatives. NUMB is an evolutionary well-conserved protein initially described as a functional </span><a href="" title="Learn more about Antagonist"><span class="ms-rteThemeForeColor-2-5 ms-rteFontSize-2">antagonist</span></a><span class="ms-rteThemeForeColor-2-5 ms-rteFontSize-2"> of NOTCH function. NUMB is an endocytic protein associated with receptor </span><a href="" title="Learn more about Internalization"><span class="ms-rteThemeForeColor-2-5 ms-rteFontSize-2">internalization</span></a><span class="ms-rteThemeForeColor-2-5 ms-rteFontSize-2">, 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 </span><a href="" title="Learn more about K562 Cells"><span class="ms-rteThemeForeColor-2-5 ms-rteFontSize-2">K562 cells</span></a><span class="ms-rteThemeForeColor-2-5 ms-rteFontSize-2"> (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 </span><a href="" title="Learn more about Programmed Cell Death"><span class="ms-rteThemeForeColor-2-5 ms-rteFontSize-2">apoptosis</span></a><span class="ms-rteThemeForeColor-2-5 ms-rteFontSize-2">mediated by the drug. Interestingly, imatinib resistance is not linked to </span><a href="" title="Learn more about Protein P53"><span class="ms-rteThemeForeColor-2-5 ms-rteFontSize-2">p53</span></a><span class="ms-rteThemeForeColor-2-5 ms-rteFontSize-2"> 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.</span><br></p><p><a href="">​Cancer Lett 375:92-99 (2016). PMID: 26944313</a><br></p>206