Exploitation of frequent deletion in the methylthioadeno-sine phosphorylase (MTAP) gene in the treatment of t-cell acute lymphoblastic leukemia (T-ALL)

MTAP is essential for the salvage of adenine and methionine. Recently, we found frequent deletion of MTAP in T-ALL patients: deletion of exon 8 of MTAP in 33.3% patients at diagnosis and 39.4% patients at relapse (AACR, in press, '96). In addition to T-ALL, MTAP deficiency has been found in many other cancers. It thus appears that MTAP deficiency in cancer may offer opportunities to develop selective therapy which would spare normal cells. Present studies analyzed the effects of an adenine synthesis inhibitor, alanosine, on MTAP(+) and MTAP(-) T cell lines, and on human hematopoietic stem/ progenitor cells. Treatment of MTAP(+) Molt 4 and MTAP(-) CEM cell lines with alanosine in the presence of 5'-dcoxyadcnosine (a substrate of MTAP), resulted in killing of MTAP(-), but not MTAP(+) cells. We also investigated whether highly purified CD34 hematopoietic stem/ progenitor cells can be rescued from alanosine toxicity by 5'deoxyadenosine, a process that requires MTAP. BFU-EV CFU-GM progenitors and the primitive HPP-CFCs from the purified CD34 cells were cultured in horse serumcontaining medium and their colony growth was found to be suppressed by incubation with 5 uM or greater concentrations of alanosine. However, in the presence of 5 to 10 uM of S'-deoxyadenosine, colony formation of hematopoietic stem/primitive progenitors was completely restored. In contrast, MTA, the endogenous substrate of MTAP was toxic to hematopoietic stem/ progenitors (IDgo < 1 u>M) presumably due to feedback inhibition of polyamine synthesis and thus could not effectively rescue cells from alanosine toxicity. Our findings indicate the presence of MTAP in human hematopoietic stem/ progenitor cells and the possibility of targeting MTAP in the design of an enzyme selective therapy for T-ALL and other MTAP-deficicnt cancers.