Kinase-inhibitor-insensitive cancer stem cells in chronic myeloid leukemia.

INTRODUCTION: Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by the translocation t(9;22), coding for the chimeric protein BCR-ABL. The development of BCR-ABL tyrosine kinase inhibitors (TKIs) has dramatically revolutionized and improved CML therapy. However, TKI-based therapy faces a major challenge: the insensitivity of CML leukemic stem cells (LSCs) to TKIs. In particular, while CML progenitor cells and differentiated cells are oncogene addicted, BCR-ABL tyrosine kinase is dispensable for CML LSC survival and maintenance. Notably, in CML, additional cellular mechanisms promote LSC survival and maintenance, rendering these cells able to survive even in the presence of TKI and to eventually promote relapse. AREAS COVERED: This review will focus on the mechanisms of LSC insensitivity to TKI and on the strategies to obtain synthetic lethality with combination therapies. EXPERT OPINION: Several pathways have been proposed to promote LSC maintenance and described as ideal targets to induce CML LSC exhaustion in combination with TKI. Ongoing clinical trials designed to target some of these pathways will assess which molecular target is relevant for in vivo human LSC survival in a new 'stem-cell targeting' perspective.