**3.2 LSCs highly express multidrug resistance genes and proteins**

The expression of multidrug resistance genes on the surface of LSCs can induce the production of various membrane transporters that can pump a variety of chemotherapeutic drugs out of the cell, which results in lowering the concentration of the drug in the cancer cells. The ABC membrane transporter plays a pivotal role in this drug efflux process. The ABC transporter, namely the ATP-binding cassette transporter, has an ATP-dependent drug-release function [34]. The most representative multidrug resistance genes are ABCB1, ABCC1, and ABCG2, which encode P-glycoproteins (P-gp, P-170, and MDR1), multidrug resistance protein (MRP), and breast cancer resistance protein (BCRP), respectively. BCRP is preferentially expressed in CD34+ CD38<sup>−</sup> LSCs. The intracellular drug concentration after BCRP inhibition is increased, but it is much lower than that of cells expressing only BCRP. Therefore, it is indicated that the drug resistance of LSC is related to the interaction of multiple drug resistance proteins. Some other reports have revealed that LSC has higher MDR1, MRP, BCRP, and lung resistance related protein (LRP) expression relative to HSC, thus giving LSC a stronger drug resistance advantage. The high expression of multidrug resistance gene in LSCs is the main mechanism by which LSCs exhibit primary resistance to chemotherapeutic drugs [35, 36].
