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 | ||
K562 cells (BCR-ABL+) | ↑ WRN and Lig III ↓ Artemis | Increased repair infidelity and survival of leukemic cells | ||
ALL | Mutations in LIG IV, ATM, and NBS1 | Development of disease | ||
↑ 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 | |||
Polymorphisms in XRCC6 and XRCC1 | Ethnic-dependent increased risk of ALL | |||
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 | ||
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 | ||
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 | ||
MDS | MDS | ↑ Defective C-NHEJ ↑ A-EJ ↓ Lig IV, Ku70, and Ku80 | A contingently ineffective increase in C-NHEJ | |
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 | |
ERCC1 | Prediction of response to melphalan and cisplatin | [133] |