Response: Could mutations in the hypoxanthine-guanine phosphoribosyl transferase gene induced by thiopurine therapy promote the development of second malignant neoplasms?

Response

The primary cytotoxic metabolite of 6-mercaptopurine (6MP) and other thiopurines are the 6-thioguanine nucleotides (6TGN), which are incorporated into DNA. Thus, during 6MP/methotrexate (MTX) therapy, 1 in 10³ to 10⁴ DNA nucleotides of circulating cells are substituted 6TGN,¹  which may interfere with postreplicative DNA mismatch repair and induce therapy-related malignant clones.^2,3  Such clones may arise very early in therapy, that is, months or years before the therapy-related cancer becomes clinically overt.⁴  It is still unknown how thiopurine therapy influences the proliferation and expansion of such clones. de Boer and colleagues propose that thiopurine-induced mutations in the hypoxanthine-guanine phosphoribosyl transferase (HGPRT) gene could render these clones resistant to further 6MP therapy and thus offer them a proliferative advantage compared with their normal counterparts. Although all second cancers occurred after cessation of therapy in the Nordic Society of Paediatric Hematology and Oncology acute lymphoblastic leukemia (ALL) 92 study, the median time to diagnosis of 16 cases of therapy-related acute myeloid leukemia and myelodysplastic syndromes (t-AML/MDS) was only 3.7 years from the diagnosis of ALL.⁵  Two lines of research could clarify the natural history of thiopurine-induced t-AML/MDS. First, by identifying the exact chromosomal breakpoints of the t-AML/MDS and backtracking the emergence of such clones in archival bone marrow material taken during therapy, it will be possible to explore if these second cancers emerge before the initiation of thiopurine therapy.⁴  Second, if de Boer et al are correct in their hypothesis, we would expect a reduced level of DNA-6TGN incorporation in the HGPRT-deficient t-AML/MDS clones compared with the normal bone marrow cells when such cases occur during thiopurine therapy. Using highly specific techniques for cell sorting⁶  and sensitive methods for quantification of DNA-6TGN,¹  it will be feasible to explore if the t-AML/MDS cases that arise during thiopurine therapy contain lower DNA-6TGN levels than the remaining normal nucleated bone marrow cells.