PMID- 8874207
OWN - NLM
STAT- MEDLINE
DCOM- 19961202
LR  - 20210216
IS  - 0006-4971 (Print)
IS  - 0006-4971 (Linking)
VI  - 88
IP  - 8
DP  - 1996 Oct 15
TI  - Frequent deletion in the methylthioadenosine phosphorylase gene in T-cell acute 
      lymphoblastic leukemia: strategies for enzyme-targeted therapy.
PG  - 3083-90
AB  - Methylthioadenosine phosphorylase (MTAP), an enzyme essential for the salvage of 
      adenine and methionine, is deficient in a variety of cancers, including acute 
      lymphoblastic leukemia (ALL). Because the MTAP gene is located adjacent to the 
      tumor-suppressor gene p16 on chromosome 9p21 and more than 60% of T-cell ALL 
      (T-ALL) patients have deletion in the p16 gene, we examined the status of the 
      MTAP gene in T-ALL patients. Quantitative polymerase chain reaction amplification 
      of exon 8 of MTAP showed a deletion in 16 of 48 (33.3%) patients at diagnosis and 
      in 13 of 33 (39.4%) patients at relapse. Southern blot analysis showed that, in 
      addition to deletion of the entire MTAP gene, a common break point was between 
      exons 4 and 5, resulting in deletion of exons 5 through 8. The finding of 
      frequent deficiency of MTAP in T-ALL offers the possibility of an enzyme targeted 
      therapy for T-ALL. MTAP(-) T-ALL-derived cell line, CEM cells were very sensitive 
      to methionine deprivation, with cell viability at 50% of control as early as 48 
      hours after methionine deprivation. In contrast, methionine deprivation had 
      little effect on the viability of normal lymphocytes or on their proliferative 
      response to phytohemagglutinin. Alanosine, an inhibitor of AMP synthesis, 
      inhibited the growth of both MTAP(+) (Molt-4 and Molt-16) and MTAP(-) (CEM and 
      HSB2) cell lines. However, the addition of methylthioadenosine, the substrate of 
      MTAP, protected the MTAP(+) cells but not the MTAP(-) cells from alanosine 
      toxicity. These findings suggest the possibility of targeting MTAP for selective 
      therapy of T-ALL.
FAU - Batova, A
AU  - Batova A
AD  - University of California San Diego, USA.
FAU - Diccianni, M B
AU  - Diccianni MB
FAU - Nobori, T
AU  - Nobori T
FAU - Vu, T
AU  - Vu T
FAU - Yu, J
AU  - Yu J
FAU - Bridgeman, L
AU  - Bridgeman L
FAU - Yu, A L
AU  - Yu AL
LA  - eng
GR  - DK 49888/DK/NIDDK NIH HHS/United States
GR  - FDA 001129/FD/FDA HHS/United States
GR  - U10CA28439/CA/NCI NIH HHS/United States
GR  - etc.
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (Antimetabolites, Antineoplastic)
RN  - 0 (DNA, Neoplasm)
RN  - 0 (Neoplasm Proteins)
RN  - 2CNI71214Y (alanosine)
RN  - 415SHH325A (Adenosine Monophosphate)
RN  - AE28F7PNPL (Methionine)
RN  - EC 2.4.2.1 (Purine-Nucleoside Phosphorylase)
RN  - EC 2.4.2.28 (5'-methylthioadenosine phosphorylase)
RN  - OF5P57N2ZX (Alanine)
SB  - IM
MH  - Adenosine Monophosphate/biosynthesis
MH  - Alanine/analogs & derivatives/pharmacology
MH  - Antimetabolites, Antineoplastic/pharmacology
MH  - Chromosomes, Human, Pair 9/genetics
MH  - DNA Mutational Analysis
MH  - DNA, Neoplasm/genetics
MH  - Exons/genetics
MH  - Genes
MH  - Genes, Tumor Suppressor
MH  - Humans
MH  - Leukemia-Lymphoma, Adult T-Cell/*genetics/pathology
MH  - Methionine/pharmacology
MH  - Neoplasm Proteins/*genetics
MH  - Polymerase Chain Reaction
MH  - Purine-Nucleoside Phosphorylase/*genetics
MH  - *Sequence Deletion
MH  - T-Lymphocytes/drug effects
MH  - Tumor Cells, Cultured/drug effects
EDAT- 1996/10/15 00:00
MHDA- 1996/10/15 00:01
CRDT- 1996/10/15 00:00
PHST- 1996/10/15 00:00 [pubmed]
PHST- 1996/10/15 00:01 [medline]
PHST- 1996/10/15 00:00 [entrez]
AID - S0006-4971(20)61549-X [pii]
PST - ppublish
SO  - Blood. 1996 Oct 15;88(8):3083-90.