Role of Pten in leukemia stem cells

Abstract

Chronic myeloid leukemia (CML) is initiated from the BCR-ABL-expressing leukemia stem cells (LSCs). These LSCs are highly resistant to BCR-ABL kinase inhibitors, imatinib, dasantinib and nilotinib, and methods for eradication of LSCs are still not available. It is critical to identify genes that play roles in survival and proliferation of LSCs. We recently discovered that the tumor suppressor gene Pten is downregulated in LSCs of CML mice. By genetic deletion or overexpression of Pten, we confirmed that Pten functions as a tumor suppressor in LSCs of CML, consistent with the role of Pten in LSCs of acute myeloid leukemia (AML) and progenitor cells of T-ALL progenitors. Functional enhancement of the Pten pathway provides a therapeutic strategy for targeting LSCs.

Figure 1.. Molecular pathways in LSCs of CML

In LSCs, BCR-ABL activates multiple signaling pathways that are normally activated by a receptor tyrosine kinase (RTK). In particular, the PI3K and Wnt/β-catenin pathways are critically involved. The novel Alox5 pathway we identified plays a specific role in LSCs but not normal HSCs (see the text for detail), and this pathway may interacts with the tumor suppressor gene Pten. The functional relationship between Alox5 and Pten is an important research topic that needs to be studied further.