Critical molecular pathways in cancer stem cells of chronic myeloid leukemia

Abstract

Inhibition of BCR-ABL with kinase inhibitors in the treatment of Philadelphia-positive (Ph(+)) chronic myeloid leukemia (CML) is highly effective in controlling but not curing the disease. This is largely due to the inability of these kinase inhibitors to kill leukemia stem cells (LSCs) responsible for disease relapse. This stem cell resistance is not associated with the BCR-ABL kinase domain mutations resistant to kinase inhibitors. Development of curative therapies for CML requires the identification of crucial molecular pathways responsible for the survival and self-renewal of LSCs. In this review, we will discuss our current understanding of these crucial molecular pathways in LSCs and the available therapeutic strategies for targeting these stem cells in CML.

Figure 1. Mouse model for studying BCR-ABL leukemia

There are three major types of mouse models of CML. a. BCR-ABL transgenic model. Inducible expression of BCR-ABL controlled by tTA tet-off system in BCR-ABL transgenic mouse. b. Retroviral bone marrow transduction/transplantation model. Bone marrow cells from 5-FU treated donor mice are transduced with BCR-ABL retrovirus, cultured in the presence of cytokines, and then transplanted into lethally irradiated syngeneic recipient mice. c. Human xenograft NOD/SCID mouse model. Bone marrow or peripheral blood cells from CML patients are purified for CD34+ cells, and then the cells are transplanted into NOD/SCID mice.