• An overview of the treatment of chronic myeloid leukemia based on its genetic profile
  • Zahra Ranjbarpoor,1,*
    1. Msc of Molecular Genetic Department of Genetics, Zanjan Branch, Islamic Azad University, Zanjan, Iran.


  • Introduction: The Philadelphia chromosome, which contains the BCR-ABL oncogene, is a unique genetic defect that has been linked to the first human cancer, chronic myeloid leukemia (CML). In the field of hematologic neoplasia, it has since evolved into a paradigm for the identification of molecular mechanisms and focused therapeutic strategies. Other significant motifs in the Abl portion include the protein-interaction SH2 and the C-terminal nuclear localization signal (NLS), DNA- and actin-binding domains. This study's objective was to look at potential treatments for chronic myeloid leukemia based on gene profiles.
  • Methods: This study on the cellular and molecular basis of cancer and chronic myeloid leukemia based on gene profiles used scientific databases including Science Direct, Springer, Google Scholar, and PubMed.
  • Results: Results showed A hematological condition known as chronic myeloid leukemia (CML) is characterized by the malignant proliferation of bone marrow stem cells. A reciprocal t(9;22)(q34;q11) chromosomal translocation that results in the Philadelphia (Ph) chromosome, a derived 9q+ and a minor 22q-, is its cytogenetic distinguishing feature. The expression of the latter has been demonstrated to be both required and sufficient for the altered phenotype of CML cells. It contains the BCR-ABL fusion gene, which encodes a chimeric Bcr-Abl protein with an unregulated tyrosine kinase activity. Among human malignancies, CML is unique in that just one oncogene product has been found to play a significant role in its pathophysiology. The molecular and cell biology of CML has been extensively studied over the past 20 years thanks to the contributions of many researchers, providing the crucial foundation for the development of targeted therapy. It quickly became apparent that the Bcr-Abl oncoprotein is the best molecular target offered by CML cells because normal cells do not express it. In addition, the analysis of the signal transduction pathways impacted by Bcr-aberrant Abl's kinase activity revealed additional or alternative signaling stages that could be blocked to reverse the oncogenic effects of Bcr-Abl. Recently, immunological methods of identifying and eliminating leukemic clone have also received attention. These methods appear promising, especially in the context of eradicating residual disease following various forms of "debulking" therapy. Although early 1990s studies were focused on attempting to block BCR-ABL gene function via its RNA message, this approach was never successfully converted into effective CML treatments. The exploration of small compounds that could interact with and inhibit this oncoprotein was thus moved to when the structure and mechanisms of action of the Bcr-Abl protein, the end result of the chromosomal translocation, were clarified. In CML, one of the two BCR-ABL junctions, called e13a2 (formerly b2a2) and e14a2 (previously b3a2), is typically present in the mRNA molecules that are transcribed from the hybrid gene. An oncoprotein with a molecular weight of 210 kDa is produced from both mRNAs. The tyrosine kinase activity of the usually controlled Abl protein is constitutively triggered by the pairing of "alien" Bcr sequences, which gives the p210Bcr-Abl its leukemogenic potential. Bcr acts by promoting dimerization of the oncoprotein such that the 2 adjacent Bcr-Abl molecules phosphorylate their respective partners on tyrosine residues in their kinase activation loops. By interacting with several effector proteins, the unchecked kinase activity of Bcr-Abl then usurps the physiological functions of the regular Abl enzyme, leading to uncontrolled cellular proliferation, decreased adherence of leukemia cells to the bone marrow stroma, and decreased apoptotic response to mutagenic stimuli. It is currently unclear how much each of these factors contributes to the phenotype of chronic phase CML.
  • Conclusion: The SH1 domain of Bcr-Abl is an obvious molecular target since it is crucial to the leukemogenicity of the oncoprotein. An isoflavonoid called genistein and an antibiotic called herbimycin-A were found to be possible candidates in early tests of natural products for substances capable of inhibiting this catalytic activity. Adenosine triphosphate (ATP) or a substrate can compete with synthetic molecules with competitive chemical structures for occupancy of the binding site in the kinase domain. This has been the subject of subsequent research.
  • Keywords: chronic myeloid leukemia, genetic profile, Philadelphia chromosome