title: New Developments in Chronic Myeloid Leukemia: Implications for Therapy.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
authors.affiliation: Cancer Research Center, Shahid Beheshti University of Medical Sciences, Tehran, IR Iran.
authors.forename: Sanaz
authors.initials: S
authors.lastname: Tabarestani
authors.affiliation: Medical Genetics Department, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, IR Iran.
authors.forename: Abolfazl
authors.initials: A
authors.lastname: Movafagh
keywords: BCR-ABL1; Chronic Myeloid Leukemia; Imatinib; Tyrosine Kinase Inhibitors