Table 3.

Acquired DDR alterations in hematologic malignancies and their functional consequences

GeneMalignancyFrequencyDriverGene functionValidated or putative pathogenic mechanism
ATM CLL 11% (mut); 13% (del)23  Validated Master regulator of DDR that recognizes DSBs and coordinates cellular response, involving cell cycle arrest, DSB repair, and/or apoptosis. Atm deletion cooperates with mutant Sf3b1 to induce CLL.37 Loss of Atm leads to high-risk CLL in Eμ:TCL1 mice.38 ATM deficiency promotes the development of DLBCL in T-cell deficient mice.39  
MCL 34% (mut); 29% (del)24  
T-PLL 54% (mut); 65% (del)25  
DLBCL 7.2% (mut or del)26  
SMZL 7.8% (mut)27  
MM 4.7% (mut or del)28  
CHEK2 T-PLL 4% (mut)25  Putative Induces G1 cell cycle arrest and prevents entry into mitosis in response to DNA DSBs.  
SMZL 1.1% (mut)27  
ATR MM 1% (mut)28  Putative Master regulator of DDR that recognizes SSBs and replication stress, leading to cell cycle arrest and stabilization of replication forks. ATR downregulation supports early tumor development in Myc–driven lymphoma models but can be tumor-suppressive at later stages.40 Consequences of ATR mutations have yet to be confirmed in MM. 
TP53 AML 6% (mut); 5% (del)29  Validated In response to DNA DSBs activates the G2 cell cycle checkpoint. Activates apoptosis in the presence of excess DNA DSBs. CRISPR drop-out screen identifies p53 as a tumor suppressor in DLBCL.26,Trp53 loss cooperates with 5q and Flt3 haploinsufficiency to induce AML in mice.41 Loss of Trp53 leads to high-risk CLL in Eμ:TCL1 mice.38  
CML BC 7.5% (mut), 13% (del)30  
ALL 2.9% (mut)31  
CLL 9.1% (mut); 6.7% (del)23  
MCL 31% (mut); 34% (del)24  
DLBCL 10% (mut or del)26  
SMZL 11% (mut)27  
FL 12% (mut)32  
BRCA1 DLBCL 3.1% (mut)33  Putative Facilitates assembly of HRR proteins BRAC1 and PALB2 mutations may induce BRCAness and genomic instability (putative). 
PALB2 AML 5.2% (del)34  Putative Acts as a hub to bring together BRCA1, BRCA2, and RAD51, thereby facilitating HRR. BRAC1 and PALB2 mutations may induce BRCAness and genomic instability (putative). 
RAD21 AML 4.2% (mut)29  Putative Cohesin complex. Redistributes unfired replication origins along the chromatin loops and prevents early initiation of dormant origins. Regulates sister-chromatid cohesion, homologous recombination, and DNA looping important for organization of the genome. Cohesin complex acts as a growth regulator of HSCs. Cohesin mutations perturb the balance between HSC self-renewal and differentiation.42  
SMC1A 2.7% (mut)35  
SMC3 2.9% (mut)35  
STAG2 2.9% (mut)29  
DYRK1A CLL 1% (mut)23  Putative Inhibits accumulation of 53BP1 at DSB sites, thereby promoting HRR in preference to NHEJ. DYRK1A mutations may lead to hyperactive HRR and chromosome dysfunction (putative). 
BRCC3 CLL 1.5% (mut)23  Putative Sequesters BRCA1 away from DSBs and promotes NHEJ in preference to HRR. BRCC3 mutations may lead to hyperactive NHEJ and genomic instability (putative). 
SMZL 0.7% (mut)27  
SAMHD1 CLL 1.4% (mut)23  Putative Regulates cellular nucleoside pools and mediates the processing of stalled replication forks. SAMHD1 mutations may exacerbate replication stress and genomic instability (putative). 
MCL 4% (mut)24  
SMZL 1.9% (mut)27  
RNASEH2B CLL 34% (monoallelic del);36  Putative Mediates RER and resolution of R-loops. In the absence of functional RNase H2, ribonucleotides are removed through an error-prone, TOP1-mediated microhomology-directed repair process that results in 2-5 bp deletions and genomic instability.43  
14% (biallelic del)36  
ARID1A ALL 1.1% (mut)31  Putative Component of the chromatin remodeling complex SWI/SNF. Regulates G2/M cell cycle checkpoint, promotes DSB resection, and activates ATR. ARID1A mutations may promote tumor initiation through deregulating gene expression and developmental programs (putative). 
GeneMalignancyFrequencyDriverGene functionValidated or putative pathogenic mechanism
ATM CLL 11% (mut); 13% (del)23  Validated Master regulator of DDR that recognizes DSBs and coordinates cellular response, involving cell cycle arrest, DSB repair, and/or apoptosis. Atm deletion cooperates with mutant Sf3b1 to induce CLL.37 Loss of Atm leads to high-risk CLL in Eμ:TCL1 mice.38 ATM deficiency promotes the development of DLBCL in T-cell deficient mice.39  
MCL 34% (mut); 29% (del)24  
T-PLL 54% (mut); 65% (del)25  
DLBCL 7.2% (mut or del)26  
SMZL 7.8% (mut)27  
MM 4.7% (mut or del)28  
CHEK2 T-PLL 4% (mut)25  Putative Induces G1 cell cycle arrest and prevents entry into mitosis in response to DNA DSBs.  
SMZL 1.1% (mut)27  
ATR MM 1% (mut)28  Putative Master regulator of DDR that recognizes SSBs and replication stress, leading to cell cycle arrest and stabilization of replication forks. ATR downregulation supports early tumor development in Myc–driven lymphoma models but can be tumor-suppressive at later stages.40 Consequences of ATR mutations have yet to be confirmed in MM. 
TP53 AML 6% (mut); 5% (del)29  Validated In response to DNA DSBs activates the G2 cell cycle checkpoint. Activates apoptosis in the presence of excess DNA DSBs. CRISPR drop-out screen identifies p53 as a tumor suppressor in DLBCL.26,Trp53 loss cooperates with 5q and Flt3 haploinsufficiency to induce AML in mice.41 Loss of Trp53 leads to high-risk CLL in Eμ:TCL1 mice.38  
CML BC 7.5% (mut), 13% (del)30  
ALL 2.9% (mut)31  
CLL 9.1% (mut); 6.7% (del)23  
MCL 31% (mut); 34% (del)24  
DLBCL 10% (mut or del)26  
SMZL 11% (mut)27  
FL 12% (mut)32  
BRCA1 DLBCL 3.1% (mut)33  Putative Facilitates assembly of HRR proteins BRAC1 and PALB2 mutations may induce BRCAness and genomic instability (putative). 
PALB2 AML 5.2% (del)34  Putative Acts as a hub to bring together BRCA1, BRCA2, and RAD51, thereby facilitating HRR. BRAC1 and PALB2 mutations may induce BRCAness and genomic instability (putative). 
RAD21 AML 4.2% (mut)29  Putative Cohesin complex. Redistributes unfired replication origins along the chromatin loops and prevents early initiation of dormant origins. Regulates sister-chromatid cohesion, homologous recombination, and DNA looping important for organization of the genome. Cohesin complex acts as a growth regulator of HSCs. Cohesin mutations perturb the balance between HSC self-renewal and differentiation.42  
SMC1A 2.7% (mut)35  
SMC3 2.9% (mut)35  
STAG2 2.9% (mut)29  
DYRK1A CLL 1% (mut)23  Putative Inhibits accumulation of 53BP1 at DSB sites, thereby promoting HRR in preference to NHEJ. DYRK1A mutations may lead to hyperactive HRR and chromosome dysfunction (putative). 
BRCC3 CLL 1.5% (mut)23  Putative Sequesters BRCA1 away from DSBs and promotes NHEJ in preference to HRR. BRCC3 mutations may lead to hyperactive NHEJ and genomic instability (putative). 
SMZL 0.7% (mut)27  
SAMHD1 CLL 1.4% (mut)23  Putative Regulates cellular nucleoside pools and mediates the processing of stalled replication forks. SAMHD1 mutations may exacerbate replication stress and genomic instability (putative). 
MCL 4% (mut)24  
SMZL 1.9% (mut)27  
RNASEH2B CLL 34% (monoallelic del);36  Putative Mediates RER and resolution of R-loops. In the absence of functional RNase H2, ribonucleotides are removed through an error-prone, TOP1-mediated microhomology-directed repair process that results in 2-5 bp deletions and genomic instability.43  
14% (biallelic del)36  
ARID1A ALL 1.1% (mut)31  Putative Component of the chromatin remodeling complex SWI/SNF. Regulates G2/M cell cycle checkpoint, promotes DSB resection, and activates ATR. ARID1A mutations may promote tumor initiation through deregulating gene expression and developmental programs (putative). 

ALL, acute lymphoblastic leukemia; BC, blast crisis; bp, base pair; CML, chronic myeloid leukemia; del, deletion; FL, follicular lymphoma; MCL, mantle cell lymphoma; MM, multiple myeloma; mut, mutation; RER, ribonucleotide excision repair; SMZL, splenic marginal zone lymphoma; SSB, single-strand break; T-PLL, T-cell prolymphocytic leukemia.

View Large
This Feature Is Available To Subscribers Only

or Create an Account

Close Modal
Close Modal