acute lymphoblastic leukemia ( all ) is an aggressive hematological tumor resulting from the malignant transformation of lymphoid progenitors . despite intensive chemotherapy , 20% of pediatric and over 50% of adult all patients fail to achieve a complete remission or relapse after intensified chemotherapy , making disease relapse and resistance to therapy the most significant challenge in the treatment of this disease1,2 . using whole exome sequencing , here we identify mutations in the cytosolic 5'-nucleotidase ii gene ( nt5c2 ) , which encodes a 5'-nucleotidase enzyme responsible for inactivation of nucleoside analog chemotherapy drugs , in 20/103 ( 19% ) relapse t - alls and in 1/35 ( 3% ) relapse 
 b - precursor alls analyzed . 
 nt5c2 mutant proteins show increased nucleotidase activity in vitro and conferred resistance to chemotherapy with 6-mercaptopurine and 6-thioguanine when expressed in all lymphoblasts . 
 these results support a prominent role for activating mutations in nt5c2 and increased nucleoside analog metabolism in disease progression and chemotherapy resistance in all .