. 2022 Jul 30;10(8):1841. doi: 10.3390/biomedicines10081841

Table 3.

Combination therapeutic approaches against LSC-enriched cells in AML and CML.

Malignancy	Combination Regimen	Mechanism of Action	Type of LSC-Enriched Population Targeted	Reference
AML	Venetoclax + 8-chloro-adenosine	Decreased fatty acid oxidation and OXPHOS	CD34⁺CD38⁻ primary AML blasts	[163]
	Venetoclax + Azacitidine	Decreased electron transport chain complex II function and OXPHOS	CD34⁺CD38⁻Lin⁻CD123⁺ AML LSCs	[143]
	Venetoclax + SLC-391	Perturbation of OXPHOS	CD34⁺ AML stem and progenitor cells	[230]
	Venetoclax + GDC-0980 (PI3K/mTOR inhibitor)	Inactivation of AKT/mTOR/p70S6K and induction of intrinsic apoptosis	CD34⁺CD38⁻CD123⁺ AML stem and progenitor cells	[243]
	Venetoclax + CT7001 (CDK7 inhibitor)	LSC-targeting mechanism likely involves the disruption of dynamic coordination of GPR56 with Wnt, hedgehog, and epithelial-mesenchymal transition signaling network	Sustained suppression of PDX human CD34⁺GPR56⁺ AML cells isolated from NSG murine BM	[244]
	AT-101 (BCL-2 inhibitor) + idarubicin	Inhibition of DNA damage repair	CD34⁺CD38⁻ KG1α and Kasumi-1 cell lines; CD34⁺ primary cells	[245]
	Tenovin-6 + quizartinib (AC220)	Inhibition of SIRT1-mediated downregulation of p53	FLT-ITD⁺ CD34⁺ AML progenitors	[136]
	Chidamide + apatinib	Reduction of mitochondrial oxidative metabolism	CD34⁺CD38⁻ KG1α cells;CD34⁺ primary AML cells	[246]
	BAY1436032 (mutant IDH1 inhibitor) + azacitidine	Decreased MAP kinase and retinoblastoma/E2F signaling and downregulation of 11 genes from LSC17 gene panel	AML leukemic stem cells characterized by serial limiting dilution transplantation	[247]
CML	DA + bosutinib	Synergistic apoptotic induction and blockage of LYN, KIT, and PDGFRα kinase signaling	Patient-derived CD34⁺CD38⁻ CML stem cells	[248]
	QLT0267 + DA	Downregulation of OXPHOS to sensitize primitive TKI-resistant CML cells	Refractory, quiescent CD34⁺ and CD34⁺CD38⁻ CML patient LSCs	[180]
	Plasminogen activator inhibitor-1 (PAI-1) TM5614 + imatinib	Displacement of CML LSCs from the protective BM microenvironment	Lin⁻c-kit⁺Sca-1⁺ CML LSC cells	[249]
	Lys05/PIK-III (autophagy inhibitors) + NL	Loss of quiescence of CML stem cells	CD34⁺CD133⁺ primary CML cells	[250]
	MRT403 (ULK1/2 inhibitor) + IM	Loss of quiescence and increase of ROS by inducing metabolic shift from glycolysis to oxidative metabolism	CD34⁺ primary CML cells	[251]
	Tenovin-6 + IM	Increase in p53 acetylation and p53-mediated transcriptional activity	CD34⁺CD38⁻ and CD34⁺CD38⁺ stem and primitive CML progenitor cells	[252]
	MAKV-8 (HDAC inhibitor) + IM	Reduction of c-MYC expression; decreased BCR-ABL and STAT5 phosphorylation	CD34⁺CD38⁻ primary CML cells	[253]
	Venetoclax + NL	Cooperative inhibition of BCL-2 and BCL-X_L/MCL-1 by nilotib and Venetoclax	CML bulk, CD34⁺CD38⁻, CD34⁺CD38⁺, and quiescent CD34⁺ blast crisis patient cells	[240]
	LB100/LB102 + IM/DA	Disruption of AHI-1-mediated signaling, particularly β-catenin	CD34⁺ CML stem and progenitor patient cells	[241]