Presence of methylthioadenosine phosphorylase (MTAP) in hematopoietic stem/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 MTAP in T-cell acute lymphoblastic leukemia (T-ALL) patients both at diagnosis and at relapse (A. Batova et al., Blood, 88: 3083-3090, 1996). In addition, MTAP deficiency has been reported in other cancers. Thus, MTAP deficiency in cancer may offer opportunities for developing selective therapy, which would spare normal cells. It is therefore important to document the presence of MTAP activity in hematopoietic stem/progenitor cells. Our approach was to investigate whether hematopoietic stem/progenitor cells can be rescued from the cytotoxicity of an AMP synthesis inhibitor, L-alanosine, by 5'-deoxyadenosine, a process that requires MTAP. Erythroid burst-forming unit, granulocyte/monocyte colony-forming unit, or granulocyte/erythrocyte/macrophage/megakaryocyte colony-forming unit progenitors and the primitive high proliferative potential colony-forming cells in the purified CD34(+) cells were cultured in horse serum-containing medium, and their colony growth was found to be suppressed by incubation with 5 microM or greater concentrations of L-alanosine. However, in the presence of 5-10 microM of 5'-deoxyadenosine, colony formation of hematopoietic stem/primitive progenitors was restored. On the other hand, 5'-deoxy-5'-methylthioadenosine, the endogenous substrate of MTAP, was toxic to hematopoietic stem/progenitors (ID50 < 1 microM), presumably due to inhibition of methylation reactions or polyamine synthesis. We also compared the effects of L-alanosine and 5'-deoxyadenosine on MTAP (+) and MTAP (-) T-ALL cell lines. Treatment 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 possibility of targeting MTAP in the design of an enzyme-selective therapy for T-ALL and other MTAP-deficient malignancies.
Yu
J
J
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, USA.
Batova
A
A
Shao
L
L
Carrera
C J
CJ
Yu
A L
AL
D000409:Alanine / Q000031:analogs & derivatives / Q000633:toxicity; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects; D003114:Colony-Forming Units Assay; D003839:Deoxyadenosines / Q000494:pharmacology; D015195:Drug Design; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics / Q000473:pathology*; D011683:Purine-Nucleoside Phosphorylase / Q000032:analysis / Q000172:deficiency / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay
D000903:Antibiotics, Antineoplastic; D003839:Deoxyadenosines; C000082:alanosine; D011683:Purine-Nucleoside Phosphorylase; C021784:5'-methylthioadenosine phosphorylase; D000409:Alanine