Diamond-Blackfan Anemia Predisposing to Myelodysplastic Syndrome in Early Adulthood

Simkins, Aron; Bannon, Sarah A.; Khoury, Joseph D.; Kanagal‐Shamanna, Rashmi; Foglesong, Jessica; Alvarado, Yesid; Borthakur, Gautam; DiNardo, Courtney D.

doi:10.1200/po.17.00112

Cited by 12 publications

(8 citation statements)

References 31 publications

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“…15 The muta tional spec trum lead ing to MDS/AML has not been sys tem at i cally or func tion ally stud ied in DBA. Somatic muta tions in TP53 and PPM1D in MDS have been reported in spo radic case reports, [16][17][18] which raises a pos si bil ity that sim i lar mech a nisms may drive malig nant trans for ma tion in DBA and SDS.…”

Section: Shwachmandiamond Syn Dromementioning

confidence: 88%

Mechanisms of somatic transformation in inherited bone marrow failure syndromes

2021

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Inherited bone marrow failure syndromes (IBMFS) cause hematopoietic stem progenitor cell (HSPC) failure due to germline mutations. Germline mutations influence the number and fitness of HSPC by various mechanisms, for example, abnormal ribosome biogenesis in Shwachman-Diamond syndrome and Diamond-Blackfan anemia, unresolved DNA cross-links in Fanconi anemia, neutrophil maturation arrest in severe congenital neutropenia, and telomere shortening in short telomere syndrome. To compensate for HSPC attrition, HSPCs are under increased replication stress to meet the need for mature blood cells. Somatic alterations that provide full or partial recovery of functional deficit implicated in IBMFS can confer a growth advantage. This review discusses results of recent genomic studies and illustrates our new understanding of mechanisms of clonal evolution in IBMFS.

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Section: Shwachmandiamond Syn Dromementioning

confidence: 88%

Mechanisms of somatic transformation in inherited bone marrow failure syndromes

2021

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“…Two analyses from the Diamond Blackfan Anemia Registry of North America (DBAR) have quantified DBA as a cancer predisposition syndrome of moderate cancer penetrance 2,3 . Smaller cohorts are consistent with this observation 4–6 . Patients with DBA have a 4.8‐fold higher relative risk of developing cancer than the general population with an overall cumulative incidence of 13.7% by age 45 years, excluding myelodysplastic syndrome (MDS) 3 .…”

Section: Introductionmentioning

confidence: 99%

Colorectal cancer screening and surveillance strategy for patients with Diamond Blackfan anemia: Preliminary recommendations from the Diamond Blackfan Anemia Registry

Lipton

Molmenti

Hussain

et al. 2021

Pediatric Blood & Cancer

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Diamond Blackfan anemia (DBA) is a rare inherited bone marrow failure syndrome characterized by red cell failure, congenital anomalies, poor linear growth, and cancer predisposition. Two previous analyses from the Diamond Blackfan Anemia Registry have quantified DBA as a cancer predisposition syndrome of moderate cancer penetrance. Patients with DBA have a 4.8-fold higher relative risk of developing cancer with an overall cumulative incidence of 13.7% by age 45 years. The two most prevalent solid tumors are colorectal cancer (CRC) and osteogenic sarcoma. Current and evolving data support the institution of cancer screening and surveillance strategies for CRC in DBA.

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“…While the mechanisms of erythroid failure in DBA are not fully defined, even less is known about the impact of RP haploinsufficiency on HSPCs. Patients with DBA are predisposed to developing age-related pancytopenia (5,6), myelodysplastic syndrome and myeloid leukemia (3,4,28).…”

Section: Introductionmentioning

confidence: 99%

“…Diamond-Blackfan anemia (DBA) is a rare congenital bone marrow failure disorder that typically presents in infancy as macrocytic anemia and erythroblastopenia ( 1 , 2 ). DBA is associated with physical anomalies such as cleft palate, renal and cardiac defects, growth retardation, and an increased risk for certain cancers ( 3 , 4 ). Although hypoplastic anemia is the dominant feature in children, bone marrow hypocellularity, pancytopenia, and immunodeficiency can develop in older patients, suggesting hematopoietic stem cell (HSC) impairment ( 5 , 6 ).…”

Section: Introductionmentioning

confidence: 99%

An RPS19-edited model for Diamond-Blackfan anemia reveals TP53-dependent impairment of hematopoietic stem cell activity

Bhoopalan¹,

Yen²,

Mayuranathan³

et al. 2023

JCI Insight

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Diamond-Blackfan anemia (DBA) is a genetic blood disease caused by heterozygous loss-offunction mutations in ribosomal protein (RP) genes, most commonly RPS19. The signature feature of DBA is hypoplastic anemia occurring in infants, although some older patients develop multi-lineage cytopenias with bone marrow hypocellularity. The mechanism of anemia in DBA is not fully understood and even less is known about the pancytopenia that occurs later in life, in part because patient hematopoietic stem and progenitor cells (HSPCs) are difficult to obtain, and the current experimental models are suboptimal. We modeled DBA by editing healthy human donor CD34 + HSPCs with CRISPR/Cas9 to create RPS19 haploinsufficiency. In vitro differentiation revealed normal myelopoiesis and impaired erythropoiesis, as observed in DBA.After transplantation into immunodeficient mice, bone marrow repopulation by RPS19 +/− HSPCs was profoundly reduced, indicating hematopoietic stem cell (HSC) impairment. The erythroid and HSC defects resulting from RPS19 haploinsufficiency were partially corrected by transduction with an RPS19-expressing lentiviral vector or by Cas9 disruption of TP53. Our results define a tractable, biologically relevant experimental model of DBA based on genome-editing of primary human HSPCs and they identify an associated HSC defect that emulates the pan-hematopoietic defect of DBA.

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Diamond-Blackfan Anemia Predisposing to Myelodysplastic Syndrome in Early Adulthood

Cited by 12 publications

References 31 publications

Mechanisms of somatic transformation in inherited bone marrow failure syndromes

Mechanisms of somatic transformation in inherited bone marrow failure syndromes

Colorectal cancer screening and surveillance strategy for patients with Diamond Blackfan anemia: Preliminary recommendations from the Diamond Blackfan Anemia Registry

An RPS19-edited model for Diamond-Blackfan anemia reveals TP53-dependent impairment of hematopoietic stem cell activity

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