Molcular-target chemotherapy in ATL using MTAP-gene deficiency

成人T细胞白血病（ATL）是最具侵袭性的淋巴组织增生性疾病之一，目前尚无标准的化疗方案来治愈这种疾病。由于甲基硫代腺苷磷酸化酶（MTAP）是一种重要的腺嘌呤和甲硫氨酸补救酶，因此预期MTAP基因缺陷的细胞对甲硫氨酸饥饿或从头嘌呤合成抑制剂变得更敏感。Southern杂交和实时PCR分析的主要ATL样品表明，超过20%的ATL病例有MTAP基因的纯合性缺失。利用本实验室建立的ATL细胞系，我们研究了MTAP基因靶向治疗是否适用于ATL。MTAP阴性细胞系（SO 4、ST 1、KK 1）对甲硫氨酸饥饿的敏感性高于MTAP阳性细胞系（KOB、OMT）。类似地，1-丙氨核苷，腺苷一磷酸（AMP）合成的抑制剂，表现出更强的细胞毒活性与MTAP阳性细胞株相比，MTAP阴性细胞株。虽然正常的淋巴细胞耐1-丙氨酸核苷治疗，原代ATL细胞表现出高敏感性1-丙氨酸核苷的MTAP基因状态无关。这些结果支持单独使用1-丙氨酸核苷或与1-甲硫氨酸酶（一种甲硫氨酸裂解酶，目前正在进行临床试验）联合使用，用于治疗MTAP阴性ATL。

Adult T-cell leukemia (ATL) is one of the most aggressive lymphoproliferative diseases and there is no standard chemotherapy regimen to achieve cure of this disease. Since methylthioadenosine phosphorylase (MTAP) is an important enzyme for the salvage of adenine and methionine, cells deficient for MTAP gene is expected to become more sensitive to methonine starvation or de novo purine synthesis inhibitors. Southern blot and real-time PCR analyses of the primary ATL samples showed that more than 20% of ATL cases have homozygous deletion of the MTAP gene. Using ATL cell lines established in our laboratory, we investigated whether MTAP-gene targetted therapy is applicable to ATL. MTAP- negative cell lines (SO4, ST1, KK1) showed higher sensitivities to methionine starvation than MTAP-positive cell lines (KOB, OMT). Similarly, 1-alanosine, an inhibitor of adenosine monophosphate (AMP) synthesis, showed stronger cytotoxic activity to MTAP-negative cell lines compared with MTAP-positive cell lines. Although normal lymphocytes were resistant to 1-alanosine treatment, primary ATL cells showed high sensitivity to 1-alanosine irrespective of MTAP-gene status. These results support the use of 1-alanosine alone or in combination with 1-methioninase, a methionine cleaving enzyme which is now under clinical trials, for the treatment of MTAP-negative ATL.