Complication free survival long-term after hemopoietic cell transplantation in thalassemia

Angelucci, Emanuele

doi:10.3324/haematol.2018.196071

Cited by 8 publications

(15 citation statements)

References 18 publications

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“…In comparison with other indications for allogeneic HSCT, there is an unexplained increased risk of graft rejection, including cases of late rejection, and mixed chimerism. 14,15 We have recently characterized MSCs from thalassemic patients for their biological and functional properties, showing their impaired capacity for hematopoietic support. 16 In this respect, understanding the HSC-niche interaction will offer the possibility of optimizing the clinical approach.…”

Section: Introductionmentioning

confidence: 99%

Hematopoietic stem cell function in β-thalassemia is impaired and is rescued by targeting the bone marrow niche

Aprile

Gulino

Storto

et al. 2020

Blood

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Hematopoietic stem cells (HSCs) are regulated by signals from the bone marrow (BM) niche, which tune hematopoiesis at steady state and in hematologic disorders. To understand the HSC-niche interactions in altered non-malignant homeostasis, we elected as a paradigm β-thalassemia, a hemoglobin disorder. In this severe congenital anemia, secondary alterations to the primary hemoglobin defect have a potential impact on HSC-niche crosstalk. Here we report that HSCs in thalassemic mice (th3) have an impaired function, caused by the interaction with an altered BM niche. The HSC self-renewal defect is rescued upon transplantation into a normal microenvironment, thus proving the active role of BM stroma. Consistently with the common finding of osteoporosis in patients, we found reduced bone deposition with decreased levels of parathyroid hormone (PTH), which is a key regulator of bone metabolism but also of HSC activity. In vivo activation of PTH signaling through the reestablished Jagged1 and osteopontin levels correlates with the rescue of the functional pool of th3 HSCs by correcting HSC-niche crosstalk. Reduced HSC quiescence is confirmed in thalassemic patients, along with altered features of the BM stromal niche. Our findings uncover a defect of HSCs in β-thalassemia induced by an altered BM microenvironment and provide new relevant insight for improving transplantation and gene therapy approaches.

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Section: Introductionmentioning

confidence: 99%

Hematopoietic stem cell function in β-thalassemia is impaired and is rescued by targeting the bone marrow niche

Aprile

Gulino

Storto

et al. 2020

Blood

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“…In comparison to other indications for allogeneic HSCT, there is an unexplained increased risk of graft failure, including cases of late rejection and mixed chimerism [ 156 , 157 ]. Especially in the autologous gene therapy HSCT, where both the donor HSCs and the recipient BM niche are diseased, the additive effect of an impaired HSC function and a defective supporting activity by the BM niche components, worsened by age and disease progression, can hamper the engraftment of genetically modified HSCs.…”

Section: Targeting the Hsc Niche In Bthal And Scdmentioning

confidence: 99%

Targeting the Hematopoietic Stem Cell Niche in β-Thalassemia and Sickle Cell Disease

et al. 2022

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In the last decade, research on pathophysiology and therapeutic solutions for β-thalassemia (BThal) and sickle cell disease (SCD) has been mostly focused on the primary erythroid defect, thus neglecting the study of hematopoietic stem cells (HSCs) and bone marrow (BM) microenvironment. The quality and engraftment of HSCs depend on the BM microenvironment, influencing the outcome of HSC transplantation (HSCT) both in allogeneic and in autologous gene therapy settings. In BThal and SCD, the consequences of severe anemia alter erythropoiesis and cause chronic stress in different organs, including the BM. Here, we discuss the recent findings that highlighted multiple alterations of the BM niche in BThal and SCD. We point out the importance of improving our understanding of HSC biology, the status of the BM niche, and their functional crosstalk in these disorders towards the novel concept of combined therapies by not only targeting the genetic defect, but also key players of the HSC–niche interaction in order to improve the clinical outcomes of transplantation.

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“…Detailed surveillance and intervention guidelines in this area have been published and should be followed to assure complication‐free cure after allo‐HCT . It is important to re‐emphasize that transplantation is always encouraged in early first few years of life …”

Section: Ex‐thalassemics—importance Of Surveillance and Interventionsmentioning

confidence: 99%

Advances in transplantation and gene therapy in transfusion-dependent β-thalassemia

Angelucci

Abutalib

2018

Adv Cell Gene Ther

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Transfusion-dependent thalassemia occurs globally and represents a major growing health problem worldwide. In majority, the disorder involves deficient or absent synthesis of the β-globin chains that constitute hemoglobin molecules and results in chronic hemolytic anemia. Subjects with the disorder must adhere to continuous red blood cell replacement program to sustain life; unfortunately such approach comes with undesirable and life-threatening complications. Without regular transfusions, thalassemic patients are prone to develop skeleton deformities, hepatosplenomegaly, and iron overload. Allogeneic hematopoietic cell transplantation preferably from HLAmatched sibling donor is widely accepted curative therapy. Gene therapy, although at its infancy, is emerging as an alternate curative option, however, with its own unique challenges. This article aims to review advances, challenges, controversies, and future prospects of allogeneic hematopoietic cell transplantation and gene therapy in subjects with transfusion dependent β-thalassemia. K E Y W O R D S

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Complication free survival long-term after hemopoietic cell transplantation in thalassemia

Cited by 8 publications

References 18 publications

Hematopoietic stem cell function in β-thalassemia is impaired and is rescued by targeting the bone marrow niche

Hematopoietic stem cell function in β-thalassemia is impaired and is rescued by targeting the bone marrow niche

Targeting the Hematopoietic Stem Cell Niche in β-Thalassemia and Sickle Cell Disease

Advances in transplantation and gene therapy in transfusion-dependent β-thalassemia

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