Exploitation Of Frequent p16 Deletion In The Treatment Of T Cell Acute Lymphoblastic Leukemia

Abstract

Methylthioadenosine phosphorylase (MTAP) is essential for the salvage of both adenine and methionine. Deficiency of MTAP has been found in a variety of cancers including acute lymphoblastic leukemia (ALL). Recently, the MTAP gene has been mapped to the close proximity of tumor suppressor genes p16 and p15 which code for inhibitors of the cyclin-dependent kinases 4 and 6. We found that p16/p15 genes are frequently co-deleted in leukemic samples obtained from patients with T-cell ALL (T-ALL). Alteration of p16 gene was found in 30/49 (61%) and 22/34 (65%) of diagnosis and relapse samples, respectively. Among those samples with p16 deletion, p15 was deleted in 19 of 24 (79%) samples studied, and MTAP gene is deleted in 20/38 (53%). The finding of high frequency of MTAP deficiency in T-ALL offers an opportunity for the design of biochemically selective therapy for T-ALL. We studied the effect of methionine depletion in a T-ALL cell line, CEM, in which p16 and MTAP genes are deleted. Incubation of CEM in methionine deficient medium resulted in an initial growth inhibition followed by gradual cell death. In contrast, methionine depletion had no significant effect on the viability of normal blood mononuclear cells or proliferative response of normal T lymphocytes to PHA. In the presence or absence of methionine, the stimulation index was 90.1 ± 8.1 and 75.9 ± 7.8, respectively at 1 μg/ml PHA, and 63.7 ± 2.3 and 69.5 ± 3.9 at 2.5 μg/ml PHA. Although MTAP (-) CEM cells appear to be as sensitive as the MTAP (+) MOLT-4 cells to alanosine, an inhibitor of AMP synthesis, addition of methythioadenosine, a substrate of MTAP, protected the MTAP (+) MOLT-4 cells but not the MTAP (-) CEM cells from alanosine cytotoxicity. These findings suggest the possibility of targeting MTAP for selective therapy of T-ALL.