Molecular mechanisms of BCR::ABL1 in chronic myeloid leukaemia: From treatment-free remission to curative therapy

Abstract

Chronic myeloid leukaemia (CML) is a clonal malignancy defined by the dysregulated proliferation of granulocytic cells in the bone marrow. The aetiology is attributed to the chimeric oncogene BCR::ABL1 which is formed by the reciprocal translocation between chromosome 9 and 22, i.e., (t9;22)(q34;q11). The oncoprotein product of the gene modulates leukaemogenesis through its intrinsic tyrosine kinase activity. The management of CML has improved significantly due to the discovery of tyrosine kinase inhibitors (TKIs), making treatment-free remission possible in selected patients with durable deep molecular remission (DMR). However, the therapeutic impact of TKIs has been impaired by the occurrence of mutations within the BCR::ABL1 kinase domain which confer resistance to TKIs. Also, leukaemic stem cells (LSCs) persist in a quiescent state within the bone marrow niche. Resistance mechanisms that are not related to BCR::ABL1 include drug efflux, microenvironmental influences, and epigenetic changes. Next‑generation sequencing and digital polymerase chain reaction (dPCR) enhance the detection of mutations and minimal residual disease, although real-time quantitative polymerase chain reaction remains the validated standard for routine monitoring. Kinase domain mutations are treated with second-generation TKIs (e.g., nilotinib), third-generation TKIs (ponatinib) or allosteric inhibitors (asciminib). Emerging therapeutic strategies including combination regimens, immunotherapy, and precision medicine based on mutation profiling are currently being investigated. Most LSC- targeted and immunotherapeutic strategies remain in preclinical or early phase clinical trials. This review explores the molecular biology of BCR::ABL1, evaluates resistance mechanisms, and establishes a conceptual framework which distinguishes functional remission and from biological cure.

Keywords: Chronic myeloid leukaemia; BCR::ABL1; Tyrosine kinase inhibitor; Drug resistance; Treatment-free remission; Leukaemia stem cells; Cure

Core Tip: Chronic myeloid leukaemia is a clonal haematological malignancy with a well-defined aetiology: The Philadelphia chromosome. The backbone of therapy are the tyrosine kinase inhibitors (TKIs) which have transformed the disease from a fatal cancer into a manageable, chronic disease. The TKIs produced remarkable cytogenetic and molecular remission but they do not produce cure in about half of the patients due to the non-eradication of leukaemia stem cells. This review evaluates the molecular mechanisms underlying BCR::ABL1 signalling and leukaemia stem cell survival, providing a framework that distinguishes guideline-supported operational remission from investigational “double-hit” therapies aimed at leukaemic clone eradication.