Table 1.

Alterations of NHEJ (classical or alternative) level in hematologic malignancies

Type of malignancy	Subtype of malignancy	Involved factor ↑ = Increase ↓ = Decrease	Highlights	Ref
Leukemia	FLT3/ITD-positive AML	↓ Ku70/80, ↑ PARP-1 and DNA Lig IIIα	Disease progression and Chemoresistance	[75]
	APL	Homozygous variants of BRCA2 and XRCC5	Risk of secondary APL development	[62]
	MLL-rearranged AML	↑ PARP1	Maintenance of MLL-AF9 in Leukemia	[73]
		Coexistence of NBS1 and MLL mutations	Increase chance of secondary malignancy after treatment with DNA topoisomerase II inhibitors	[68]
	K562/DNR	↑ DNA-PKcs and Lig IV	DNR resistant More aggressive MDR phenotype	[79]
	CML	↓ DNA-PK, Lig IV, and Artemis ↑ Lig III and WRN	Progression to blast crisis	[91, 134]
	K562 cells (BCR-ABL+)	↑ WRN and Lig III ↓ Artemis	Increased repair infidelity and survival of leukemic cells	[91, 93]
	ALL	Mutations in LIG IV, ATM, and NBS1	Development of disease	[50, 51, 135]
		↑ mRNA of Ku70, Ku80, DNA-PK, Artemis, Lig IV XRCC4, and Cernunnos ↑ 53BP1/γH2AX foci	Unfaithful DSBR and increased genome instability Causing BCR-ABL and TEL-AML fusions	[57, 70, 136]
		Polymorphisms in XRCC6 and XRCC1	Ethnic-dependent increased risk of ALL	[59, 60, 137]
	KRAS-mutant T-ALL	↑ DNA Lig IIIα, PARP1, and XRCC1	Hyperactivation of more error-prone pathways (A-EJs)	[138]
	T-ALL	↑ PI3K/mTOR pathway (ATM-ATR-DNA-PK)	Poor prognosis and failure of treatment	[139]
	CLL	↑ MMEJ factor and DNA-PK	Poor survival of patients	[6, 42]
		Mutation or deletion of ATM	Chemoresistance	[140]
		↑ SSA	Telomere fusion	[45]
Lymphoma	C-MYC-driven lymphoma	↑ ATM/CHK2 ↑ ATR/CHK1	Paradoxical effects, including tumor suppression and protection of the viability of cancer cells	[100]
	Mature B cell lymphoma (FL, MCL, DLBCL, MALT, and MZL)	↑ Lig I, Lig III, PARP1, CtIP, and MRE11 ↓ C-NHEJ functional mutations in Artemis, DNA-PKcs, XRCC5, and XRCC6	High level of DSB and aberrant DSBR	[101, 102]
	DLBCL	Mutations in ATM	Inactivation of ARF as a tumor suppressor gene and P53	[141]
	Leukemic non-nodal MCL	Deletion of PARP1	Unfavourable outcome	[109]
	EBV-driven NK/T lymphoma	↓ Cernunnos (XLF)	Genomic instability	[103]
	HL	Adverse alleles of DSBR genes, including XRCC1	Genomic chaos Dicentric chromosomes resulting from telomere dysfunction and aberrant NHEJ	[142, 143]
MDS	MDS	↑ Defective C-NHEJ ↑ A-EJ ↓ Lig IV, Ku70, and Ku80	A contingently ineffective increase in C-NHEJ	[118, 144]
MM	MM	↑ DNA-PKcs, Artemis, XRCC4, and Lig IIIa ↓ XRCC6 ↑ Lig IV and XRCC4 Mutations in ATM, ATR, MRN complex, XRCC3, and XRCC4	Ineffective increase of C-NHEJ pathway	[77, 128–130]
		ERCC1	Prediction of response to melphalan and cisplatin	[133]