Targeting the Chronic Myeloid Leukemia Stem Cell: A Paradigm for the Curative Treatment of Human Malignancies

Chronic Myeloid Leukemia (CML) is a clonal myeloproliferative disorder of pluripotent hematopoietic stem/progenitor cells that has been paradigmatic to our understanding of the molecular and cellular basis of human malignancies. It has provided an excellent example of how a specific molecular abnormality can be targeted therapeutically to transform a lifethreatening malignancy into a chronic disease. The study of CML has been characterized by a number of ‘firsts’. CML was the first malignancy to be: (i) associated with a specific chromosomal abnormality, (ii) associated with a specific molecular alteration (BCR-ABL) and (iii) successfully treated with a specifically designed targeted therapeutic agent. As such it seems natural that CML should be the first human malignancy in which a complete medical cure is achieved through the eradication of cancer stem cells. This should be realizable through combining the specific targeting of BCR-ABL and CML stem cells. Once this has been achieved, the challenge will be to successfully transfer the lessons learned from this relatively simple and well-characterized model system to the eradication of cancer stem cells in more complex malignancies. The treatment of CML has changed dramatically following the introduction into the clinic of the tyrosine kinase inhibitor (TKI) imatinib mesylate and second generation TKIs. These agents directly target the BCR-ABL oncoprotein product of the constitutively active BCRABL tyrosine kinase. The specific targeting of BCR-ABL induces durable clinical remission in a high proportion of chronic phase CML (CP-CML) subjects (5 year survival of 89%) (Druker et al, 2006). Although a major molecular response (defined as a 3-log reduction in BCR-ABL mutant allele burden) is obtained in many CP-CML patients, only a small number attain PCR negativity as determined by the absence of residual BCR-ABL transcripts (Hughes et al, 2003). This is because TKI therapy does not specifically target or eliminate leukemia stem cells (LSCs). Indeed TKI therapy alone is unlikely to ever be curative, as following treatment with TKIs LSCs persist in bone marrow (BM) stem cell niches where they harbor the potential for relapse. The emergence of resistance to TKI monotherapy