Genetic analysis of chronic myeloid leukemia treated with dasatinib and rapidly developing AML with monosomy 7 in Philadelphia-negative cells

This is an author produced version of a paper published in Cancer Genetics and Cytogenetics. This paper has been peer-reviewed but does not include the final publisher proof-corrections or journal pagination. "Genetic analysis of dasatinib-treated chronic myeloid leukemia rapidly developing into acute myeloid leukemia with monosomy 7 in Philadelphia-negative cells." Abstract Despite the recent success of tyrosine kinase inhibitors (TKI) in the treatment of chronic myeloid leukemia (CML), some patients (2-17%) develop clonal cytogenetic changes in the Philadelphia (Ph-) negative cell population. A fraction of these patients, in particular those displaying trisomy 8 or monosomy 7, are at risk of developing a myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Consequently, there is a need to characterize the clinical features of such cases and to increase our understanding of the pathogenetic mechanisms underlying the emergence of clonal cytogenetic changes in Ph-negative cells. So far, most cases reported have received treatment with imatinib. Herein, we describe a patient with CML who developed monosomy 7 in Ph-negative cells during dasatinib therapy. Twenty months after dasatinib initiation, the patient developed MDS that rapidly progressed into AML. Genome-wide 500K SNP array of the monosomy 7 clone, revealed no acquired submicroscopic copy number changes. Given the strong association between monosomy 7 and mutations of genes involved in the RAS pathway in juvenile myelomonocytic leukemia, we also screened for pathogenetic variants in KRAS, NRAS, and PTPN11, but did not detect any changes.