A complex mutational signature generated by cytarabine resistance

T cell acute lymphoblastic leukemia (T-ALL) patients generally respond well to chemotherapy, but T-ALL cells at relapse are typically resistant to chemotherapy. The specific mechanisms leading to chemoresistance are incompletely understood. Here we use Mcm2 hypomorph (Mcm2hypo) T-ALL cell lines, which are prone to copy number variant mutations, to identify acquired mutations that underlie chemoresistance. We successfully generated 11 chemotherapy-resistant T-ALL cell lines, identifying excellent candidate genes responsible for resistance due to acquired mutations, including CNV, SNV, and small indels.These candidates included amplification of Abcb1a/b associated with vincristine resistance, amplification of Dhfr associated with methotrexate resistance, loss of Nr3c1 associated with prednisone resistance and loss of Dck associated with cytarabine resistance.