Chromosomal instability syndromes with inherited predisposition to hematologic malignancies
| . | Fanconi anemia . | Nijmegen breakage syndrome . | Ataxia telangiectasia . | Bloom syndrome . |
|---|---|---|---|---|
| Causative mutation | FANC genes, most commonly FANCA, FANCC, and FANCG | NBN | ATM | BLM |
| Gene function | Mediates DNA interstrand cross link repair that involves cross link detection, nucleolytic processing, translesion synthesis, HRR, and DNA duplex restoration | Recognizes DSBs through its involvement in the MRN complex, thereby activating ATM | Phosphorylates proteins to regulate DDR pathways that mediate repair of DSBs through HRR and/or NHEJ | Mediates convergent branch migration and resolution of Holliday junctions, a 4-stranded intermediate DNA structure, during homologous recombination repair of DSBs |
| Participates in DNA end resection during DNA repair | ||||
| DDR defect | Interstrand crosslink repair | DSB detection and sensing | Cellular response to DSBs | HRR |
| Cell-intrinsic effects | Chromosomal breakage and accumulation of structural variants due to unrepaired ICLs from endogenous DNA damage (eg, reactive aldehydes) Hypersensitivity to ICL-inducing agents | Chromosomal translocations and genetic instability arising from failure to repair DSBs Hypersensitivity to ionizing radiation | Chromosomal translocations and genetic instability arising from failure to repair DSBs Hypersensitivity to ionizing radiation | Defective DNA end resection and the dissolution of Holliday junctions Impaired replication fork stability and increased risk of sister-chromatid exchanges, chromosomal breakage, and rearrangements |
| Hematologic features | Bone marrow failure (90%), pancytopenia, aplastic anemia, and predisposition to MDS/AML (33% prevalence by the age of 50 y) | Predisposition to lymphoid malignancies (40% prevalence by the age of 20 y), of which 45% are B-cell lymphomas, and 55% are T-cell lymphomas | Predisposition to B and T-cell lymphoid malignancies particularly in childhood; B-NHL represents 37% of all tumors observed in patients with AT | Predisposition to leukemia (AML and ALL) and lymphoma (median age of onset, 20 y) |
| Pathogenic mechanism | Damaged HSCs are genetically unstable, and undergo senescence and p53-dependent apoptosis | Unrepaired DSBs promote meiotic and somatic recombination in cells of the adaptive immune system | Unrepaired DSBs promote meiotic and somatic recombination in cells of the adaptive immune system | Genome instability in hematopoietic cells caused by defective maintenance and dissolution of double Holliday junctions |
| Prevalence | 5 per million | Very rare worldwide but higher prevalence in central and eastern Europe | 3 per million | 2 per million |
| Inheritance | Autosomal recessive (98%) | Autosomal recessive | Autosomal recessive | Autosomal recessive |
| X-linked recessive (2%) | ||||
| Recent mechanistic and therapeutic discoveries | FA genomic signature involves structural variants enriched for deletions, duplications, and unbalanced translocations, such as trisomy MDM4 that downregulates p53, promoting clonal hematopoiesis, and leukemogenesis5,6 EXO1 limits replication stress and DNA damage in FA to counteract formaldehyde-induced ICLs and genomic instability7 | MRN complex prevents genomic instability by regulating resolution of R-loops8 MRN dimers can further dimerize during response to DNA DSBs to facilitate both catalytic and tethering functions of MRN complexes9 | ATM plays a role in the regulation of centrosome clustering and resolution of R-loops10,11 New strategies for reestablishing ATM function in vivo include splice-switching as well as suppression of nonsense mutations using tRNAs with altered anticodons12,13 | BLM helicase mediates DNA end processing through formation of large single-stranded DNA loops14 BLM syndrome protein complex functions as a hetero-tetramer that involves BLM, Topo IIIα, RMI1, and RMI2. Within that complex, truncated BLM allele can exert a dominant-negative effect15 |
| . | Fanconi anemia . | Nijmegen breakage syndrome . | Ataxia telangiectasia . | Bloom syndrome . |
|---|---|---|---|---|
| Causative mutation | FANC genes, most commonly FANCA, FANCC, and FANCG | NBN | ATM | BLM |
| Gene function | Mediates DNA interstrand cross link repair that involves cross link detection, nucleolytic processing, translesion synthesis, HRR, and DNA duplex restoration | Recognizes DSBs through its involvement in the MRN complex, thereby activating ATM | Phosphorylates proteins to regulate DDR pathways that mediate repair of DSBs through HRR and/or NHEJ | Mediates convergent branch migration and resolution of Holliday junctions, a 4-stranded intermediate DNA structure, during homologous recombination repair of DSBs |
| Participates in DNA end resection during DNA repair | ||||
| DDR defect | Interstrand crosslink repair | DSB detection and sensing | Cellular response to DSBs | HRR |
| Cell-intrinsic effects | Chromosomal breakage and accumulation of structural variants due to unrepaired ICLs from endogenous DNA damage (eg, reactive aldehydes) Hypersensitivity to ICL-inducing agents | Chromosomal translocations and genetic instability arising from failure to repair DSBs Hypersensitivity to ionizing radiation | Chromosomal translocations and genetic instability arising from failure to repair DSBs Hypersensitivity to ionizing radiation | Defective DNA end resection and the dissolution of Holliday junctions Impaired replication fork stability and increased risk of sister-chromatid exchanges, chromosomal breakage, and rearrangements |
| Hematologic features | Bone marrow failure (90%), pancytopenia, aplastic anemia, and predisposition to MDS/AML (33% prevalence by the age of 50 y) | Predisposition to lymphoid malignancies (40% prevalence by the age of 20 y), of which 45% are B-cell lymphomas, and 55% are T-cell lymphomas | Predisposition to B and T-cell lymphoid malignancies particularly in childhood; B-NHL represents 37% of all tumors observed in patients with AT | Predisposition to leukemia (AML and ALL) and lymphoma (median age of onset, 20 y) |
| Pathogenic mechanism | Damaged HSCs are genetically unstable, and undergo senescence and p53-dependent apoptosis | Unrepaired DSBs promote meiotic and somatic recombination in cells of the adaptive immune system | Unrepaired DSBs promote meiotic and somatic recombination in cells of the adaptive immune system | Genome instability in hematopoietic cells caused by defective maintenance and dissolution of double Holliday junctions |
| Prevalence | 5 per million | Very rare worldwide but higher prevalence in central and eastern Europe | 3 per million | 2 per million |
| Inheritance | Autosomal recessive (98%) | Autosomal recessive | Autosomal recessive | Autosomal recessive |
| X-linked recessive (2%) | ||||
| Recent mechanistic and therapeutic discoveries | FA genomic signature involves structural variants enriched for deletions, duplications, and unbalanced translocations, such as trisomy MDM4 that downregulates p53, promoting clonal hematopoiesis, and leukemogenesis5,6 EXO1 limits replication stress and DNA damage in FA to counteract formaldehyde-induced ICLs and genomic instability7 | MRN complex prevents genomic instability by regulating resolution of R-loops8 MRN dimers can further dimerize during response to DNA DSBs to facilitate both catalytic and tethering functions of MRN complexes9 | ATM plays a role in the regulation of centrosome clustering and resolution of R-loops10,11 New strategies for reestablishing ATM function in vivo include splice-switching as well as suppression of nonsense mutations using tRNAs with altered anticodons12,13 | BLM helicase mediates DNA end processing through formation of large single-stranded DNA loops14 BLM syndrome protein complex functions as a hetero-tetramer that involves BLM, Topo IIIα, RMI1, and RMI2. Within that complex, truncated BLM allele can exert a dominant-negative effect15 |
ALL, acute lymphoblastic leukemia; BLM, Bloom; B-NHL, B-cell non-Hodgkin lymphoma; ICLs, interstrand crosslinks; MRN, MRE11-RAD50-NBS1; RMI1, RecQ–mediated genome instability 1; RMI2, RecQ–mediated genome instability 2; Topo IIIα, DNA topoisomerase-3α; tRNA, transfer RNA.