ATRA-Induced Cellular Differentiation and CD38 Expression Inhibits Acquisition of BCR-ABL Mutations for CML Acquired Resistance

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Acquired resistance through genetic mutations is a major mechanism for cancer drug resistance and accounts for the short life of targeted therapy in several types of human cancer. Mechanistically, however, very little is understood about how resistant mutations are actually acquired during cancer therapy. In this manuscript, we used chronic myelogenous leukemia (CML) as a disease model and showed that mutation acquisition process is accompanied by global genome transcriptional reprogramming and reduction of cellular differentiation status. Forced cell differentiation by all-trans retinoic acid (ATRA) potently blocks acquisition of genetic mutations and CML acquired resistance. ATRA effect is mediated, in part, through stimulating CD38 gene expression, which reduces cellular cofactor nicotinamide adenine dinucleotide (NAD+) content and thus the activity of NAD+-dependent protein deacetylase SIRT1 that promotes error-prone DNA damage repair and mutagenesis. Our findings provide novel insight of mutation acquisition process during targeted therapy for CML. This study has translational implication in clinical treatment of CML, and perhaps other malignancies, by combining a differentiation agent to overcome mutation-mediated drug resistance if possible.

Vyšlo v časopise: ATRA-Induced Cellular Differentiation and CD38 Expression Inhibits Acquisition of BCR-ABL Mutations for CML Acquired Resistance. PLoS Genet 10(6): e32767. doi:10.1371/journal.pgen.1004414
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004414

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