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

Table 2 Comparison of resistance mechanisms in chronic myeloid leukaemia

Mechanism	BCR::ABL1 kinase-dependent resistance[47]2,[49]1	BCR::ABL1 kinase independent resistance[47]2
Pathophysiology	Intrinsic changes to BCR::ABL1 gene or protein e.g., point mutations in the tyrosine kinase domain e.g., T315I[68]1. BCR::ABL1 gene amplification or over expression. Compound mutations on the same allele causing resistance to multiple TKIs	Alternative pathways or protective niches e.g., activation of parallel oncogenic pathways e.g., STAT3, PI3/AKT, Wnt/β-catenin[47]. Quiescence of leukaemia stem cell. Altered pharmacokinetics e.g., through the overexpression of efflux transporters (ABCB1) or downregulation of influx transporters (OCT1)
Effect of dose escalating or TKI switch	Very effective	Limited efficacy because BCR::ABL1 is already suppressed
Clinical presentation	Loss of major molecular remission	Primary TKI resistance. Persistence of minimal residual disease. Failure of treatment-free remission
Diagnosis	RT-qPCR for BCR::ABL1. Sanger sequencing	Cytogenetics. Transcriptomic profiling
Management	Mutation-guided TKI switching. Allosteric binding combinations e.g., competitive TKI + asciminib. Allogeneic Haematopoietic stem cell transplantation	Combination targeted therapies e.g., TKI + BCL-2 inhibitor like venetoclax. Leukaemia stem cell eradication strategies. Allogeneic haematopoietic stem cell transplantation

¹Preclinical study.

²Review.

ABCB1: ATP-binding cassette sub-family B member 1; AKT: Serine/threonine kinase; OCT1: Organic cation transporter 1; PI3: Phosphoinositide 3; STAT3: Signal transducer and activator of transcription 3; TKI: Tyrosine kinase inhibitor.