J. Yu et al., PRESENCE OF METHYLTHIOADENOSINE PHOSPHORYLASE (MTAP) IN HEMATOPOIETICSTEM PROGENITOR CELLS - ITS THERAPEUTIC IMPLICATION FOR MTAP (-) MALIGNANCIES/, Clinical cancer research, 3(3), 1997, pp. 433-438
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.