Molecular and cellular correlates of methotrexate response in childhood acute lymphoblastic leukemia

The improved outlook for children diagnosed today with acute lymphoblastic leukemia (ALL) over that 40 years ago is remarkable. With modern therapies and supportive care, complete remissions are achieved in up to 95% of patie nts and long-term disease-free survival rates approach 80%. Methotrexate is a key component in ALL consolidation and maintenance therapies and is admi nistered intrathecally in the prophylaxis and treatment of central nervous system leukemia. Recent reports have significantly extended the results of preclinical studies of methotrexate response and resistance to patients wit h ALL. The application of new and sensitive molecular biology techniques ma kes it possible to study specific chromosomal and genetic alterations [t(12 ;21), hyperdiploidy, deletions or methylation of p15(INK4B) and p16(INk4A)] which potentially contribute to methotrexate response and resistance in ch ildhood. All. Studies of the relationships between genetic alterations and ALL progression, methotrexate pharmacology, and long term event-free-surviv als may lead Co the better identification of subgroups of patients who exhi bit unique levels of sensitivity or resistance to chemotherapy including me thotrexate. Further, by characterizing the roles of translocation-generated fusion genes (TEL-AML1) and tumor suppressor genes (p15(INK4B) and p16(INK 4A)) in treatment response, it may be possible to identify new and selectiv e targets and/or treatment strategies for both children and adults with ALL who are refractory to current therapies.