Clonal evolution mechanisms in NT5C2 mutant-relapsed acute lymphoblastic leukaemia.

Area of Science:

• * Hematology
• * Molecular Biology
• * Cancer Research

Background:

• * Relapsed acute lymphoblastic leukemia (ALL) presents poor prognosis and chemotherapy resistance.
• * Gain-of-function mutations in the 5'-nucleotidase, cytosolic II (NT5C2) gene are linked to 6-mercaptopurine resistance in relapsed ALL.
• * Mechanisms of NT5C2 mutation-driven clonal evolution in leukemia initiation, progression, and relapse are not fully understood.

Purpose of the Study:

• * To investigate the role of NT5C2 mutations in the clonal evolution of relapsed ALL.
• * To elucidate the mechanisms by which NT5C2 mutations confer chemotherapy resistance.
• * To explore potential therapeutic strategies targeting NT5C2-mutant ALL.

Main Methods:

• * Utilized a conditional-and-inducible leukemia model in mice.
• * Introduced the prevalent NT5C2(R367Q) mutation into leukemia cells.
• * Assessed chemotherapy resistance, cell growth, and leukemia-initiating cell activity.
• * Analyzed purine metabolism and extracellular purine export.
• * Evaluated the efficacy of inosine-5'-monophosphate dehydrogenase (IMPDH) inhibition.

Main Results:

• * Expression of NT5C2(R367Q) conferred resistance to 6-mercaptopurine chemotherapy.
• * NT5C2 mutation led to impaired leukemia cell growth and reduced leukemia-initiating cell activity, indicating a fitness cost.
• * Mutant cells exhibited excessive extracellular purine export and depleted intracellular purine-nucleotide pools.
• * Inhibition of IMPDH significantly increased cytotoxicity against NT5C2-mutant leukemia lymphoblasts.

Conclusions:

• * NT5C2 mutations impose a fitness cost on leukemia cells, influencing clonal evolution.
• * Chemotherapy resistance and fitness cost are key drivers in relapsed ALL evolution.
• * IMPDH inhibition represents a potential therapeutic approach for treating NT5C2-mutant ALL.