Relapsed acute lymphoblastic leukaemia (ALL) is associated with resistance to chemotherapy and poor prognosis1. Gain-of-function mutations in the 5′-nucleotidase, cytosolic II (NT5C2) gene induce resistance to 6-mercaptopurine and are selectively present in relapsed ALL2,3. Yet, the mechanisms involved in NT5C2 mutation-driven clonal evolution during the initiation of leukaemia, disease progression and relapse remain unknown. Here we use a conditional-and-inducible leukaemia model to demonstrate that expression of NT5C2(R367Q), a highly prevalent relapsed-ALL NT5C2 mutation, induces resistance to chemotherapy with 6-mercaptopurine at the cost of impaired leukaemia cell growth and leukaemia-initiating cell activity. The loss-of-fitness phenotype of NT5C2+/R367Q mutant cells is associated with excess export of purines to the extracellular space and depletion of the intracellular purine-nucleotide pool. Consequently, blocking guanosine synthesis by inhibition of inosine-5′-monophosphate dehydrogenase (IMPDH) induced increased cytotoxicity against NT5C2-mutant leukaemia lymphoblasts. These results identify the fitness cost of NT5C2 mutation and resistance to chemotherapy as key evolutionary drivers that shape clonal evolution in relapsed ALL and support a role for IMPDH inhibition in the treatment of ALL.
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We are grateful to R. Kopan for the ΔE-NOTCH1 construct and T. Ludwig for the ROSA26Cre-ERT2/+ mouse. This work was supported by the Leukemia & Lymphoma Society Quest for Cures (R0749-14) and Translational Research (6455-15; 6531-18) awards (A.A.F.), an Innovative Research Award from the Alex Lemonade Stand Foundation (A.A.F.), the Chemotherapy Foundation (A.A.F.), National Institutes of Health (NIH) grants R35 CA210065 (A.A.F.), R01 CA206501 (A.A.F.), U54 CA193313 (R.R.), R01 CA185486 (R.R.), U54 CA209997 (R.R.), U10 CA98543 (J.M.G., M.L.L.), P30 CA013696, the Human Specimen Banking Grant U24 CA114766 (J.M.G.), the Stewart Foundation (R.R.) and the American Lebanese Syrian Associated Charities of St Jude Children’s Research Hospital. G.T. was supported by a HHMI International Student Research Fellowship. M.S.M. was supported by a Rally Foundation fellowship. C.L.D. was supported by NIH/NCI T32-CA09503. J.Y. was supported by the China Scholarship Council (CSC 201304910347) and the Ter Meulen Grant of the Royal Netherlands Academy of Arts and Sciences. E.W. was supported by the Dutch Cancer Society (KUN2012-5366).
Extended data figures
Metabolomic Analysis of Nt5c2+/R367Q and Nt5c2+/co-R367Q ALL lymphoblasts.
Metabolomic Analysis of Nt5c2+/R367Q and Nt5c2+/co-R367Q ALL conditioned media.
Metabolomic Analysis of NT5C2 WT and NT5C2 R367Q expressing CUTLL1 and REH Cells.
Metabolomic Analysis of Conditioned Media from NT5C2 WT and NT5C2 R367Q expressing CUTLL1 and REH Cells.