Molecular determinants of treatment response in acute lymphoblastic leukemia.

Abstract

Treatment response in patients with acute lymphoblastic leukemia (ALL) is best assessed using assays for minimal residual disease (MRD). The degree of leukemia cytoreduction and MRD clearance is determined by the collective influence of multiple factors. Some of these variables are features of the leukemic cells, such as expression of genes that regulate their susceptibility to cytotoxic drugs and their propensity to undergo apoptosis. Gene profiles depend, in turn, on the cell of origin for leukemic transformation, the type of underlying genetic abnormalities and/or epigenetic regulatory mechanisms. Another set of variables is related to the host, such as age and polymorphisms in genes that metabolize drugs, which together with pharmacologic variables, such as drug pharmacodynamics and drug interactions, influence treatment response. Finally, the bone marrow microenvironment where leukemic cells reside can participate in the generation of drug resistance. Altogether, these variables determine treatment outcome in each patient. Full knowledge of the molecular features associated with treatment response is required for precise leukemia prognostication and monitoring, and can provide clues to useful targets for novel therapies.