Chronic myeloid leukemia (CML) is a hematologic neoplasm characterized by the expression of the BCR::ABL1 oncoprotein, a constitutively active tyrosine kinase, resulting in uncontrolled growth and proliferation of cells in the myeloid lineage. Targeted therapy using tyrosine kinase inhibitors (TKIs) such as imatinib, nilotinib, dasatinib, bosutinib, ponatinib and asciminib has drastically improved the life expectancy of CML patients. However, treatment resistance occurs in 10–20% of CML patients, which is a multifactorial problem that is only partially clarified by the presence of TKI inactivating BCR::ABL1 mutations. It may also be a consequence of a reduction in cytosolic TKI concentrations in the target cells due to transporter-mediated cellular distribution. This review focuses on drug-transporting proteins in stem cells and progenitor cells involved in the distribution of TKIs approved for the treatment of CML. Special attention will be given to ATP-binding cassette transporters expressed in lysosomes, which may facilitate the extracytosolic sequestration of these compounds.

The distribution of tyrosine kinase inhibitors (TKIs) used in the treatment of chronic myeloid leukemia (CML) is influenced by the efflux transporters P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP). While most TKI-transporter interactions are well established, limited information is available for the novel STAMP inhibitor asciminib, and divergent data exist for the role of P-gp in nilotinib and bosutinib efflux. This study used in vitro cellular and vesicular transport assays to evaluate the substrate and inhibitory profiles of all TKIs currently used in CML treatment. It was confirmed that asciminib is a substrate of both P-gp and BCRP, similar to imatinib and dasatinib, whereas bosutinib was modestly transported by P-gp only. For P-gp, asciminib appeared to be a weak inhibitor, comparable to dasatinib, whereas nilotinib remained the most potent inhibitor. Conversely, asciminib demonstrated notable potency against BCRP, ranking it among the strong inhibitors imatinib, nilotinib, and ponatinib, while dasatinib and bosutinib were less effective. These findings provide further insight into the efflux transporter interactions of asciminib and updated evidence on nilotinib and bosutinib transport by P-gp, with implications for drug resistance and treatment optimization in CML.

Resistance to tyrosine kinase inhibitor therapy in patients with chronic myeloid leukemia remains a clinical challenge of which the underlying mechanisms are not always fully understood. The leukemic bone marrow microenvironment is increasingly recognized as an important factor protecting leukemic cells from therapeutic pressure. However, studying this leukemic bone marrow is complicated by limited accessibility of the bone marrow in vivo and the limited physiological relevance of conventional in vitro disease models. Microfluidic bone-marrow-on-a-chip models provide a platform for reconstructing the cellular, biochemical, and biophysical components of the bone marrow niche under controlled conditions. These models may more accurately recapitulate the in vivo microenvironment while avoiding some of the limitations inherent in animal models. Their ability to mimic the bone marrow niche provides novel opportunities to investigate the complex interactions between leukemic cells and their microenvironment. Moreover, the incorpora-tion of patient-derived cells highlights the potential of personalized chronic myeloid leu-kemia-on-a-chip models to study interpatient heterogeneity in treatment response. This review explores the potential of chronic myeloid leukemia-on-a-chip models as platforms for basic research and clinical translation.