Constitutive Activation of Tyrosine Kinase by Oligomerization of BCR-ABL1, Allosteric Effect and Adaptor Proteins in Chronic Myeloid Leukemia and Novel Therapeutic Strategies

Introduction of orthosteric tyrosine kinase inhibitors (TKIs) targeting BCR-ABL1 has drastically improved prognosis of the patients with CML at chronic phase (CML-CP). However, once blast crisis occurs, conventional therapies including TKIs become ineffective to leukemia stem cells (LSCs) of CML. Thus substantially different therapeutics strategies are required. This review article is aimed at summarizing the mechanisms of BCR-ABL1 oligomerization, allosteric effect on its conformation and adaptor proteins around BCR-ABL1. Then, novel therapeutic strategies against CML LSCs based on these three upstream activation mechanisms of the BCR-ABL1 were shown. Oligomerization of BCR-ABL1 is required for constitutive activation of tyrosine kinase. Allosteric effect on conformation change of BCR-ABL1 induces autophosphorylation of BCR-ABL1 that is required for binding of adaptor proteins that mediate signal transduction. Thus inhibitors targeting the BCR coiled-coil (CC) domains that induce oligomerization, allosteric inhibitors and inhibitors against adaptor proteins are the promising therapeutic strategies to overcome various types of therapy resistance in CML. However, detailed investigations and trials are further required.