Literature Review of Hematology Division The Mechanism of Imanitib Resistance in Chronic Myeloid Leukemia

Abstract

Chronic Myeloid Leukemia (CML) refers to a kind of malignancycharacterized by the clonal proliferation of myeloid leukocytes in the bone marrow. The World Health Organization (WHO) classifies CML as a Myeloproliferative Neoplasm (MPN) identified by the proliferation of granulocyte cells without differentiation disorders. As a result, peripheral blood smears display varying levels of differentiation within the granulocyte series. Furthermore, the translocation between chromosomes 9 and 22 gives rise to the Philadelphia chromosome (Ph) (BCR-ABL1). Imatinib mesylate (GleevecTM), a chemotherapeutic belonging to the protein kinase inhibitor group, is the first-generation Tyrosine Kinase Inhibitor (TKI) used for treating chronic phase CML. Imatinib mesylate suppresses cancer cell signals and inhibits a sequence of chemical events that contribute to cell growth and development. It achieves this by binding to the ATP binding region, trapping it in a self-inhibited or closed conformation, and exerting non-competitive suppression on protein enzyme activities. Consequently, this procedure leads to the inhibition of leukemogenesis-promoting signaling pathways.Imatinib resistance poses a significant challenge, and it can be classified as primary or secondary resistance based on the onset time. Depending on the mechanism, resistance can be characterized as BCR-ABL1-independent or BCR-ABL1-dependent. The most prevalent mechanism of imatinib resistance is the mutation of the ABL kinase domain, followed by BCR-ABL1 amplification and overexpression. In cases of inadequate response or treatment failure, the European Leukemia Network (ELN) recommends mutation screening before transitioning to second-generation Tyrosine Kinase Inhibitors (TKIs). Mutations of the BCR-ABL1 kinase domain can be analyzed using alternative examination methods such as Sanger sequencing, Next-Generation Sequencing (NGS), and digital Polymerase Chain Reaction (dPCR).Various methods have been employed to enhance therapy response or treat TKI-resistant patients, including increasing the dose of Imatinib, utilizing next-generation Tyrosine Kinase Inhibitors, and resorting to bone marrow transplantation.