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The immunomodulatory drug Leflunomide inhibits cell cycle progression of B-CLL cells

Leukemia volume 22, pages 635–638 (2008)Cite this article

Chronic lymphocytic leukemia (CLL) is a heterogeneous disease characterized by the accumulation of mature B cells incapable of undergoing apoptosis. Constitutively activated signaling proteins, such as phosphatidylinositol 3 (PI3)-kinase and Protein kinases C (PKCs), contribute to the defect of the programmed cell death. It has also become increasingly evident that a distinct compartment of proliferative cells account for the progression of the disease. Such dividing B-CLL cells can be found in the so-called proliferation centers in the spleen and bone marrow of CLL patients, although the underlying signals that drive cells into the cell cycle are not well defined. While disease progression is dependent on proliferative B-CLL cells rather than on G1-arrested cells, therapies aimed at blocking cell cycle progression seem to be a new and striking approach to the treatment of CLL patients.

Leflunomide (SU101 or HWA 486) is a novel isoaxzole derivate that in vivo becomes rapidly converted to its active metabolite A77 1726. Because the drug has an antiproliferative effect on human T cells, it was introduced in the treatment of rheumatoid arthritis and other autoimmune diseases. Leflunomide specifically inhibits the activity of dihydro-orotate dehydrogenase (DHODH) in a non-competitive manner.1 DHODH is the rate-limiting enzyme in the de novo biosynthesis of pyrimidines. While its antiproliferative effect on lymphocytes and mononuclear cells is completely reversible by exogenous uridine, blockade of DHODH is considered to be the main mode of action. However, other targets have been defined and may contribute to the inhibitory effects of Leflunomide regardless of the availability of pyrimidines: Leflunomide inhibits platelet-derived growth factor receptor-mediated signal transduction including tyrosine phosphorylation and cell cycle progression. Importantly, doses required to block tyrosine phosphorylation are approximately 10- to 100-fold higher than those needed to block pyrimidine synthesis.2 However, some reports have pointed to other potential effects of Leflunomide, including downregulation of cytokine production and decreased expression of cytokine receptors.

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  1. 3rd Department of Medicine, Technical University of Munich, Munich, Germany

    I Ringshausen, M Oelsner, C Bogner, C Peschel & T Decker

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  1. I Ringshausen
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  2. M Oelsner
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  3. C Bogner
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Correspondence to I Ringshausen.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Ringshausen, I., Oelsner, M., Bogner, C. et al. The immunomodulatory drug Leflunomide inhibits cell cycle progression of B-CLL cells. Leukemia 22, 635–638 (2008). https://doi.org/10.1038/sj.leu.2404922

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