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增生性疾病之一，目前尚无标准的化疗方案可治愈。由于甲硫腺苷磷酸化酶(MTAP)是回收腺嘌呤和蛋氨酸的重要酶，MTAP基因缺陷的细胞有望对蛋氨酸饥饿或从头合成嘌呤的抑制剂变得更加敏感。对原发ATL标本的Southern杂交和实时荧光定量PCR分析显示，超过20%的ATL病例存在MTAP基因的纯合缺失。利用我们实验室建立的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(SO4、ST1、KK1)对蛋氨酸饥饿的敏感性高于MTAP阳性细胞系(KOB、OMT)。类似地，腺苷一磷酸(AMP)合成抑制剂1-丙氨酸对MTAP阴性细胞株的细胞毒活性也强于MTAP阳性细胞株。虽然正常淋巴细胞对1-丙氨酸治疗有抵抗力，但原代ATL细胞对1-丙氨酸表现出高度的敏感性，而与MTAP基因状态无关。这些结果支持单独使用1-丙氨酸或与1-蛋氨酸酶联合使用，1-蛋氨酸酶是一种蛋氨酸裂解酶，目前正在进行临床试验，用于治疗MTAP阴性的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.