Turning on healthy stem cells, turning off leukemia

Sydney, Australia -

The signals that control proliferation of hematopoietic stem cells are still relatively unknown. Not only is the study of the hematopoietic stem cell important because it is one of the most well characterized stem cell systems, but also it has some very strong practical implications in terms of treating disease. For example, hematopoietic toxicity is often the dose-limiting factor in treating cancer with chemotherapy or radiation therapy. Therefore there is great interest in compounds that protect bone marrow stem cells, as well as approaches to increase stem cell proliferation. One of the interesting ways of stimulating proliferation of hematopoietic stem cells is through inhibiting the enzyme Glycogen Synthase Kinase-3{beta} (GSK-3). Essentially, GSK-3 is involved in degrading beta catenin a stimulator of hematopoietic stem cell proliferation so the idea is that if you inhibit the inhibitor you will get stimulation.

In a recent paper (Holmes et al. Glycogen Synthase Kinase-3{beta} inhibition Preserves Hematopoietic Stem Cell activity and Inhibits Leukemic Cell Growth. Stem Cells. 2008 Mar 6), inhibition of GSK-3 was performed and various molecular pathways where assessed in response to the inhibition using hematopoietic stem cells as a model.

The authors demonstrated that

- inhibition of GSK-3 upregulated expression of HOXB4

- inhibition of GSK-3 resulted in retained LTCIC activity

- inhibition of GSK-3 increased contact between hematopoietic stem cells and the bone marrow stroma

- inhibition of GSK-3 induced apoptosis in leukemia cells, prolly through downregulating survivin

The ability of compounds to turn on healthy hematopoiesis but to kill leukemic hematopoiesis is a very strange phenomena. This is also observed in vitro with valproic acid