engleski

Sensitivity of acute myeloid leukemia primary cells to AICAr-mediated differentiation

Differentiation therapy is a promising treatment strategy for treating acute myeloid leukemia (AML) and most successful example is all-trans-retinoic acid (ATRA)-based therapy of acute promyelocytic leukemia (APL). Nucleotide biosynthesis pathway has been recently identified as a novel differentiation target in AML and the inhibitors of dihydroorotate dehydrogenase (DHODH), a fourth step in de novo pyrimidine synthesis, are currently being tested in Phase I clinical trials. Our previous work demonstrated that 5-aminoimidazole-4- carboxamide ribonucleoside (AICAr) induced differentiation of monocytic leukemia cell line U937 by inhibiting UMP synthesis at the step downstream of DHODH. The aim of this study was to test the effects of AICAr on proliferation and differentiation of mononuclear cells isolated from the bone marrow of patients suffering from de novo AML. In a set of bone marrow samples from 16 patients with non-APL AML grown in vitro with the addition of IL-3, IL-6, SCF and FLT3L, AICAr induced a significant decrease in viability as measured by MTT assay. In one sample (FAB-M2, normal male karyotype, FLT3wt NPM1wt, primary refractory), the addition of AICAr resulted in a pronounced increase in the expression of differentiation markers CD11b and CD64 as well as accumulation of cells that morphologically resembled macrophages. An increase in the levels of differentiation markers in this sample was observed in response to brequinar, but not ATRA. In conclusion, AICAr exhibits profound antiproliferative effects in primary AML samples in vitro. Preliminary data suggest for the existence of a potential subpopulation of AML patients in which both AICAr and brequinar could induce differentiation.

AML ; primary cells ; differentiation ; AICAr

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