PRESENCE OF METHYLTHIOADENOSINE PHOSPHORYLASE (MTAP) IN HEMATOPOIETICSTEM PROGENITOR CELLS - ITS THERAPEUTIC IMPLICATION FOR MTAP (-) MALIGNANCIES/

Methylthioadenosine phosphorylase (MTAP) is important for the salvage of adenine and methionine, Recently, we found frequent deletion of MTA P in T-cell acute lymphoblastic leukemia (T-ALL) patients both at diag nosis and at relapse (A, Batova et al., Blood, 88: 3083-3090, 1996), I n addition, MTAP deficiency has been reported in other cancers, Thus, MTAP deficiency in cancer may offer opportunities for developing selec tive therapy, which would spare normal cells. It is therefore importan t to document the presence of MTAP activity in hematopoietic stem/prog enitor cells. Our approach was to investigate whether hematopoietic st em/progenitor cells can be rescued from the cytotoxicity of an AMP syn thesis inhibitor, L-alanosine, by 5'-deoxyadenosine, a process that re quires MTAP, Erythroid burst-forming unit, granulocyte/monocyte colony -forming unit, or granulocyte/erythrocyte/macrophage/megakaryocyte col ony-forming unit progenitors and the primitive high proliferative pote ntial colony-forming cells in the purified CD34(+) cells were cultured in horse serum-containing medium, and their colony growth was found t o be suppressed by incubation with 5 mu M or greater concentrations of L-alanosine, However, in the presence of 5-10 mu M of 5'-deoxyadenosi ne, colony formation of hematopoietic stem/primitive progenitors was r estored. On the other hand, 5'-deoxy-5'-methylthioadenosine, the endog enous substrate of MTAP, was toxic to hematopoietic stem/progenitors ( ID50 < 1 mu M), presumably due to inhibition of methylation reactions or polyamine synthesis. We also compared the effects of L-alanosine an d 5'-deoxyadenosine on MTAP (+) and MTAP (-) T-ALL cell lines. Treatme nt of MTAP (+) Molt 4 and MTAP (-) CEM cell lines with L-alanosine in the presence of 5'-deoxyadenosine resulted in killing of MTAP (-), but not MTAP (+) cells. Therefore, our findings demonstrate the presence of MTAP in human hematopoietic stem/progenitor cells and support the p ossibility of targeting MTAP in the design of an enzyme-selective ther apy for T-ALL and other MTAP-deficient malignancies.