Methylthioadenosine phosphorylase deficiency in acute leukemia: pathologic, cytogenetic, and clinical features

Abstract

Blast cells from 100 cases of acute leukemia were evaluated for the presence of methylthioadenosine phosphorylase (MTAase), an enzyme important in polyamine metabolism. Ten cases (10%) had undetectable levels of MTAase activity. Of the 10, 5 had acute lymphoblastic leukemia (ALL), 3 had acute myeloblastic leukemia (AML) and 2 expressed mixed lineage markers as determined by immunophenotyping. A relatively high frequency (38%) of MTAase deficiency was seen in ALL of T-cell origin. Nonmalignant hematopoietic cells from three patients with MTAase-deficient leukemias had readily detectable enzyme activity. Chromosomal abnormalities were detected in four of the seven MTAase- deficient cases in which karyotypic analysis was performed. No consistent karyotypic defect was apparent, and only one case displayed changes in chromosome 9, the putative location of the MTAase structural gene. The clinical findings among the enzyme-deficient cases were unremarkable except that all patients were male (P less than .01). Only one patient had “lymphomatous” features. We conclude that MTAase deficiency occurs in a wide variety of acute leukemias, that the lack of enzyme activity is specific to the malignant cells, and that an increased incidence occurs in ALL of T-cell origin. Furthermore, no specific gross chromosomal abnormality is associated with the enzyme deficiency. The marked male predominance in patients with MTAase- deficient acute leukemias suggests involvement of the X chromosome in the loss of enzyme activity. The absence of MTAase in some leukemias may be therapeutically exploitable.

CDKN2A, CDKN2B, and MTAP gene dosage permits precise characterization of mono‐ and bi‐allelic 9p21 deletions in childhood acute lymphoblastic leukemia

“…MTAP deficiency was first reported in cell lines (Kamatani et al, 1982) and T-ALL (Traweek et al, 1988), but molecular explanations could not be given at that time. MTAP co-deletion has now been evidenced in many tumors with CDKN2A deletion, and a recurrent breakpoint has been observed between exons 4 and 5 (Batova et al, 1996).…”

6-Thioguanine: A Drug With Unrealized Potential for Cancer Therapy

“…The high frequency of homozygous deletions of MTAP in many tumors (Table 1) suggested an approach to treatment, involving 6-TG, that could be highly selective [28,29,[32][33][34][35][36][37][38][39][40][41]. The treatment takes advantage of the metabolic pathway involving MTA, the natural substrate of the enzyme MTAP.…”

“…Blood levels and incorporation into the bone marrow DNA were higher with the higher doses. After five daily doses of 6-TG, the guanine of the DNA in the bone marrow was largely [33] 50 Non-small cell lung cancer [34] 30 Sarcoma [35] 30 Glioblastoma [36] 30 Gastrointestinal tumors [37] 20 Hematologic malignancies T-cell lymphoma [28,38] 70 MCL, DLCL, AML [29,39] 5-30 Pre-B ALL [40,41] 20-30 Munshi, Lubin, Bertino replaced by 6-TG [11,12]. These drugs are often referred to as "self-limiting" because incorporation into DNA decreases when total DNA synthesis is inhibited by purine starvation.The extent of this effect varies with the tissue type or cell line being studied and the concentration of the drug.…”

Loss of 5′-Methylthioadenosine Phosphorylase (MTAP) is Frequent in High-Grade Gliomas; Nevertheless, it is Not Associated with Higher Tumor Aggressiveness

“…MTAP (5 -methyltioadenosine phosphorylase) encodes a key enzyme involved in the metabolism of polyamines and purines [17][18][19]. This enzyme converts 5 -methyltioadenosine (MTA), a by-product of polyamine biosynthesis, into adenine and MTR-1-P (methylthioribose-1-phosphate), which are recycled into AMP (adenosine monophosphate) and methionine [19,20].…”