new developments in chronic myeloid leukemia: implications for therapy

Context: chronic myeloid leukemia (cml) is a myeloproliferative disorder characterized by overproduction of immature and matured myeloid cells in the peripheral blood, bone marrow and spleen. evidence acquisition: a hallmark of cml is the presence of (9; 22) (q34; q11) reciprocal translocation, which is cytogenetically visible as philadelphia chromosome (ph) and results in the formation of bcr-abl1 fusion protein. this fusion protein is a constitutively active tyrosine kinase which is necessary and sufficient for malignant transformation. the introduction of imatinib, a bcr-abl1- targeting tyrosine kinase inhibitor (tki) has revolutionized cml therapy. subsequently, two other tkis with increased activity against bcr-abl1, dasatinib and nilotinib, were developed and approved for cml patients. nevertheless, cml therapy faces major challenges.results: the first is the development of resistance to bcr-abl1 inhibitors in some patients, which can be due to bcr-abl1 overexpression, differences in cellular drug influx and efflux, activation of alternative signaling pathways, or emergence of bcr-abl1 kinase domain mutations during tki treatment. the second is the limited efficiency of bcr-abl1-tkis in blast crisis (bc) cml. the third is the insensitivity of cml stem cells to bcr-abl1 inhibitors. conventional chemotherapeutics and bcr-abl1 inhibitors which act by inhibiting cell proliferation and inducing apoptosis, are ineffective against quiescent cml stem cells. conclusions: a better understanding of the mechanisms that underlie tki resistance, progression to bc, genomic instability and stem cell quiescence is essential to develop curative strategies for patients with cml.