Does NUMB Protein Play a Role in Imatinib-Resistant CML?
Posted: Friday, May 24, 2019
Low levels of activity of the NUMB protein may contribute to proliferation of chronic myeloid leukemia (CML) cells, perhaps imparting resistance to imatinib, according to Eva García-Alegría, PhD, of the University of Santander, Spain, and colleagues. Reduced NUMB expression has previously been implicated in other cancers and maintenance of blast crisis CML. In this recent study, published in Cancer Letters, CML cell proliferation and response to imatinib were investigated in the context of NUMB expression.
The researchers compared K562 cells constitutively expressing a dominant negative version of NUMB (KdnNUMB) with parent K562 cells using a battery of tests (bromodeoxyuridine staining, cell counting, immunoblotting, thymidine incorporation, and cell-cycle and erythroid-differentiation analysis). K562 cells were transduced with dnNUMB, constructed using a lentiviral backbone containing 163 amino acids that comprise the NUMB phosphotyrosine-binding domain.
Compared with control cells, KdnNUMB cells showed higher rates of cell proliferation; higher BCR-ABL activity; and decreased response to imatinib, dasatinib, and nilotinib, independent of NOTCH signaling. Increased differentiation and expression of erythroid genes were also induced in KdnNUMB cells, compared with control cells.
“Our data support the hypothesis that NUMB activation could be a new therapeutic target in CML,” concluded the authors.
Disclosure: The study authors’ disclosure information may be found at sciencedirect.com.