Editors' ChoiceLeukemia

Genomics of T-ALL Reveals a Weapon of an Evasive Foe

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Science Translational Medicine  27 Mar 2013:
Vol. 5, Issue 178, pp. 178ec52
DOI: 10.1126/scitranslmed.3006150

Cancer cells specialize in adapting to evolutionary pressures through acquisition of somatic mutations and clonal evolution. This ability makes cancer a formidable nemesis, because tumor cells use an arsenal of genomic mechanisms to acquire resistance to therapies. Future genomic medicine approaches may entail profiling a patient’s tumor genome on an ongoing basis and adapting treatment in concert with the tumor’s evolving resistance mechanisms.

Tzoneva et al. identified activating mutations of NT5C2 as a mechanism of chemoresistance to 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG), two drugs that are commonly used in the treatment of T cell acute lymphoblastic leukemia (T-ALL). Whole-exome sequencing of matched diagnosis, remission, and relapse samples from five pediatric T-ALL samples identified mutations of NT5C2 acquired at the time of relapse. NT5C2 mutations were observed in 22 of 98 relapsed T-ALL patients and 1 of 35 relapsed B-precursor ALL patients, but not in 23 T-ALL and 27 B-precursor ALL tumors sampled at diagnosis. The authors suggested that NT5C2 may confer chemoresistance based on its ability to inactivate metabolites mediating the cytotoxic effects of 6-MP and 6-TG. The authors demonstrated increased in vitro enzymatic activity of recombinant NT5C2 mutant proteins and used cell viability assays to demonstrate that mutant NT5C2 resulted in decreased sensitivity to 6-MP and 6-TG, but not nelarabine, a chemotherapy drug which is metabolized by a different mechanism.

The work of Tzoneva et al. has potential translational relevance by suggesting NT5C2 mutation profiling of 6-MP–resistant T-ALL patients and potential nelarabine salvage therapy. More generally, this work represents an approach to cancer molecular medicine in which comparative analysis of cancer genomes corresponding to different clinicopathologic states can identify the underlying acquired mutations and suggest precision therapies. On a sobering note, the current work only partially explains a very specific chemoresistance mechanism, and salvage therapies are likely subject to additional resistance acquired in subsequent tumor evolution. Future cancer genomic medicine may indeed be resigned to a perpetual cat-and-mouse game with little hope of catching the proverbial mouse. However, a persistent community effort to characterize chemoresistance mechanisms may equip clinicians with the tools to stay one step ahead of such an agile foe.

G. Tzoneva et al., Activating mutations in the NT5C2 nucleotidase gene drive chemotherapy resistance in relapsed ALL. Nat. Med. 19, 368–371 (2013). [Abstract]

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