Reduced-intensity conditioning is effective for hematopoietic stem cell transplantation in young pediatric patients with Diamond–Blackfan anemia

Koyamaishi, Shun; Kamio, Takeshi; Kobayashi, Akie; Sato, Tomohiko; Kudo, Ko; Sasaki, Susumu; Kanezaki, Rika; Hasegawa, Daiichiro; Muramatsu, Hideki; Takahashi, Yoshiyuki; Sasahara, Yoji; Hiramatsu, Hidefumi; Kakuda, Harumi; Tanaka, Miyuki; Ishimura, Masataka; Nishi, Masanori; Ishiguro, Akira; Yabe, Hiromasa; Takeo, Satoshi; Yamamoto, Masaki; Yuza, Yuki; Hyakuna, Nobuyuki; Yoshida, Kenichi; Kanno, Hitoshi; Ohga, Shouichi; Ohara, Akira; Kojima, Seiji; Miyano, Satoru; Ogawa, Seishi; Toki, Tsutomu; Terui, Kiminori; Ito, Etsuro

doi:10.1038/s41409-020-01056-1

Cited by 11 publications

(14 citation statements)

References 27 publications

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“…Previous studies in mice ( 30 , 77 ) and our current study with human cells show that normal or gene-corrected HSCs outcompete RPS19 +/– HSCs after transplantation. These findings suggest that reduced-intensity bone marrow conditioning may be sufficient for full engraftment of allogeneic donor ( 78 ) or autologous gene-corrected HSCs, although this approach might be avoided if the DBA recipient harbors hematopoietic cell clones with somatic mutations of TP53 or other leukemia-associated genes.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…Recent reports have described improved outcomes of HCT for DBA with long-term survival rates of more than 90% (Table 1) [44,45]. An analysis conducted by the EBMT-SAAWP involved the largest cohort of 106 patients with DBA who underwent HCT and showed similar outcomes between MRD and MUD transplants [46].…”

Section: Diamond-blackfan Anemiamentioning

confidence: 99%

“…Additionally, a more recent Japanese study has suggested promising results of unrelated CBT for DBA; the 5-year OS and EFS rates of 11 patients with DBA who received unrelated CBT were 100 and 82%, respectively [21]. Most patients have received HCT with MAC regimens for this disorder; however, recent data have shown comparable outcomes between MAC and RIC regimens, suggesting that HCT using RIC is a promising option for young patients with DBA [45]. Long-term follow-up for patients with DBA who received HCT should focus on iron overload and the development of secondary malignancies, particularly osteosarcoma and colorectal cancer.…”

Section: Diamond-blackfan Anemiamentioning

confidence: 99%

Recent advances in hematopoietic cell transplantation for inherited bone marrow failure syndromes

Sakaguchi

Yoshida²

2022

Int J Hematol

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Inherited bone marrow failure syndromes (IBMFSs) are a group of rare genetic disorders characterized by bone marrow failure with unique phenotypes and predisposition to cancer. Classical IBMFSs primarily include Fanconi anemia with impaired DNA damage repair, dyskeratosis congenita with telomere maintenance dysfunction, and Diamond-Blackfan anemia with aberrant ribosomal protein biosynthesis. Recently, comprehensive genetic analyses have been implemented for the definitive diagnosis of classic IBMFSs, and advances in molecular genetics have led to the identification of novel disorders such as AMeD and MIRAGE syndromes. Allogeneic hematopoietic cell transplantation (HCT), a promising option to overcome impaired hematopoiesis in patients with IBMFSs, does not correct nonhematological defects and may enhance the risk of secondary malignancies. Disease-specific management is necessary because IBMFSs differ in underlying defects and are associated with varying degrees of risk for clonal evolution and early or late complications after HCT. In addition, long-term follow-up is essential to detect complications related to the IBMFS or HCT. This review provides a summary of current clinical practices along with the latest data on HCT in IBMFSs.

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“…Busulfan-based RIC, melphalan-based RIC was successfully used in nine patients. 2 However, considering that the standard conditioning regimen is MAC with busulfan, the choice of a conditioning regimen without busulfan should be made with caution. Our experience suggested that a proper reduction of busulfan by pharmacokinetic tests and a compensatory intensification of conditioning, such as low-dose TBI, might reduce the risk of severe complications without increasing the risk of graft failure.…”

mentioning

confidence: 99%

“…A recent retrospective study indicated that RIC could be an effective and safe candidate in HCT for DBA. 2 Considering the interindividual variability in the pharmacokinetics, busulfan dosage should be determined according to pharmacokinetic studies, especially in HCT using RIC; 3,4 however, targeted busulfan-based RIC in HCT for DBA has not been reported. This report describes our experience on HCT using targeted busulfanbased conditioning for DBA from an unrelated donor.…”

mentioning

confidence: 99%

Transplantation using targeted busulfan for Diamond–Blackfan anemia

Kato

Nakano

Hidaka

et al. 2023

Pediatrics International

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Reduced-intensity conditioning is effective for hematopoietic stem cell transplantation in young pediatric patients with Diamond–Blackfan anemia

Cited by 11 publications

References 27 publications

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

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

Recent advances in hematopoietic cell transplantation for inherited bone marrow failure syndromes

Transplantation using targeted busulfan for Diamond–Blackfan anemia

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