Table 1.

Mechanisms of drug resistance in leukemia

Chemoresistance mechanism	Example protein/pathway	Mode of action and drugs affected	Reference/s
Drug receptor downregulation or inactivation	Glucocorticoid receptor	Reduced expression, decreased activity, internalization or receptor mutations prevents drug activity and induction of apoptosis	(64,65)
Drug efflux	ATP-binding cassette (ABC) superfamily of transporters e.g. MRP3 in ALL	Transporters mediate active efflux of a broad spectrum of cytotoxic compounds thereby reducing intracellular drug accumulation and toxicity	(5,66–69)
Intracellular drug degradation	NT5C2 cytosolic 5′ Nucleotidase II	Enzyme metabolizes and inactivates nucleoside analogs which constitute chemotherapeutic agents	(70,71)
Gene deletion/mutation	DCK/FPGS	Genetic deletions of DCK and FPGS prevent drug activation and lead to resistance against cytarabine and methotrexate respectively	(72)
Targeted protein modification	BCR/ABL	BCR/ABL kinase domain mutations confer resistance to imatinib treatments	(73)
Upregulation of proliferative proteins	A20	Overexpression of A20 leads to increased proliferation and anti-apoptotic effects in conjunction with MAPK signaling and p53 to confer chemoresistance	(74)
Cellular quiescence	Exit to G0	Intracellular signaling causes an exit from cell cycle to G0 and resistance to multiple drugs that are effective only on proliferating cells	(75)
Overexpression of negative regulators of apoptosis	GSTM1	Overexpression prevents the activity of apoptotic regulators like Bim	(76)
Ion flux	hERG1	hERG1 channel activity increased pro-survival signaling and conferred multidrug resistance	(11)
Redox adaptation	Antioxidant production and MCL-1	Increased mitochondrial calcium influx increases levels of reactive oxygen species, leading to an adaptation process that increases antioxidant and MCL-1 levels to induce multidrug resistance	(77)
Abnormal glucose metabolism	GLUT1	Increase in transporter expression increases glucose uptake and prevents cells from undergoing metabolic stress and defends against chemotherapy	(78)
Unfolded protein response	XBP1	Expression of XBP1 protects cells from ER stress and leads to chemoresistance	(79)
Increased protein expression of DNA repair proteins	Alt-NHEJ pathway	Increased activity of DNA repair pathway allows cells to repair more readily and protect against chemotherapy	(80)
Protein stabilization	p73	p73 stabilization by Kpm/Lats2 phosphorylation of YAP2 protected cells from DNA damaging chemotherapeutics	(81)
MicroRNA aberrations	miR125b/100/99a	Dysregulation of miRNAs can alter expression patterns of key proteins and lead to resistance against chemotherapy drugs like vincristine	(82)
Cell adhesion mediated drug resistance	Cell-cell/matrix adhesion	Binding of cellular adhesion molecules on the surface of ALL cells to other cells or the ECM in the BM stimulate a chemoprotective effect	(83,84)