Chronic myeloid leukemia: advances in understanding disease biology and mechanisms of resistance to tyrosine kinase inhibitors

Curr Hematol Malig Rep. 2015 Jun;10(2):158-66. doi: 10.1007/s11899-015-0248-3.


The successful implementation of tyrosine kinase inhibitors (TKIs) for the treatment of chronic myeloid leukemia (CML) remains a flagship for molecularly targeted therapy in cancer. This focused review highlights critical elements of the underlying biology of CML and provides a summary of the molecular mechanisms that lead to TKI resistance: BCR-ABL1 mutation-based resistance and therapy escape through alternative pathway activation despite inhibition of BCR-ABL1 tyrosine kinase activity. We direct attention to the most current manifestations of these issues, including emergence of pan-TKI-resistant BCR-ABL1 compound mutants, new strategies for identification and therapeutic targeting of alternative pathways, and the exciting, controversial topic of cessation of TKI therapy leading to durable treatment-free remissions for a subset of patients. Further gains in our understanding of the biology of Philadelphia chromosome-positive (Ph-positive) leukemia and mechanisms of resistance to BCR-ABL1 TKIs will benefit patients and also provide a blueprint for similar discovery in other cancers.

Publication types

  • Review

MeSH terms

  • Antineoplastic Agents / therapeutic use*
  • Drug Resistance, Neoplasm* / drug effects
  • Fusion Proteins, bcr-abl / genetics
  • Fusion Proteins, bcr-abl / metabolism
  • Humans
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy*
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / enzymology
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics
  • Molecular Targeted Therapy
  • Mutation
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / therapeutic use*
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Protein-Tyrosine Kinases / metabolism


  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Protein-Tyrosine Kinases
  • Fusion Proteins, bcr-abl