Deficiency of the ribosome biogenesis gene Sbds in hematopoietic stem and progenitor cells causes neutropenia in mice by attenuating lineage progression in myelocytes

Zambetti, Noemi A.; Bindels, Eric; Strien, Paulina M. H. van; Valkhof, Marijke; Adisty, Maria N.; Hoogenboezem, Remco M.; Sanders, Mathijs A.; Rommens, Johanna M.; Touw, Ivo P.; Raaijmakers, Marc H.G.P.

doi:10.3324/haematol.2015.131573

Cited by 52 publications

(57 citation statements)

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“…While knocking down or deleting Sbds in mouse hematopoietic progenitors impairs myeloid differentiation, decreased Sbds expression did not generate other pathologic features of MDS [64, 65]. Consequently, it has been suggested that BMME dysfunction may also contribute to the SDS hematopoietic phenotype as normal human CD34+ cells demonstrated reduced myeloid potential following co-culture with marrow stroma from SDS patients compared to normal stroma [66].…”

Section: Bone Marrow Microenvironment Defects and Mds Initiationmentioning

confidence: 99%

The microenvironment in myelodysplastic syndromes: Niche-mediated disease initiation and progression

Calvi

2017

Experimental Hematology

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Myelodysplastic syndromes (MDS) are clonal disorders of hematopoietic stem and progenitor cells and represent the most common cause of acquired marrow failure. Hallmarked by ineffective hematopoiesis, dysplastic marrow, and risk of transformation to acute leukemia, MDS remains a poorly treated disease. Although identification of hematopoietic aberrations in human MDS has contributed significantly to our understanding of MDS pathogenesis, evidence now identify the bone marrow microenvironment (BMME) as another key contributor to disease initiation and progression. With improved understanding of the BMME, we are beginning to refine the role of the hematopoietic niche in MDS. Despite genetic diversity in MDS, interaction between MDS and the BMME appears to be a common disease feature, and therefore represents an appealing therapeutic target. Further understanding of the interdependent relationship between MDS and its niche is needed to delineate the mechanisms underlying hematopoietic failure and how the microenvironment can be clinically targeted. This review will provide an overview of data from human MDS and murine models supporting a role for BMME dysfunction at several steps of disease pathogenesis. While no models or human studies so far have combined all these findings, we will review current data identifying BMME involvement in each step of MDS pathogenesis, organized to reflect the chronology of BMME contribution as the normal hematopoietic system becomes myelodysplastic and MDS progresses to marrow failure and transformation. Although microenvironmental heterogeneity and dysfunction certainly add complexity to this syndrome, data are already demonstrating that targeting microenvironmental signals may represent novel therapeutic strategies for MDS treatment.

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Section: Bone Marrow Microenvironment Defects and Mds Initiationmentioning

confidence: 99%

The microenvironment in myelodysplastic syndromes: Niche-mediated disease initiation and progression

Calvi

2017

Experimental Hematology

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“…Although for some diseases the involved Bcl-2 proteins and their upstream regulators have been characterized in detail, for other diseases their contribution can only be speculated. Interestingly, some of the disorders are initially characterized by high susceptibility to apoptosis that, [190,[192][193][194] Congenital amegakaryocytic thrombocytopenia (CAMT) [201,202] Diamond Blackfan anemia (DBA)…”

Section: The Impact Of Bcl-2 Protein Deregulation On Human Hematologimentioning

confidence: 99%

Bcl‐2 proteins in development, health, and disease of the hematopoietic system

et al. 2016

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Members of the Bcl‐2 protein family regulate cell fate decisions following a variety of developmental cues or stress signals, with the outcomes of cell death or survival, thus shaping multiple mammalian tissues. This review describes in detail how anti‐ and proapoptotic Bcl‐2 proteins contribute to the development and functioning of the fetal and adult hematopoietic systems and how they influence the generation and maintenance of different hematopoietic lineages. An overview on how stress signals such as genotoxic stress or inflammation can compromise blood cell production, partially by engaging the intrinsic apoptosis pathway, is presented. Finally, the review describes how Bcl‐2 protein deregulation—either leading to increased apoptosis resistance or excessive cell death—contributes to many hematological disorders, with specific focus on rare disorders of hematopoiesis and how this knowledge may be used therapeutically.

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“…Whereas in this way the recipients of Sbds-deficient HSCs nicely recapitulated the neutropenia phenotype of human SDS, the myelodysplasia, which is another hematologic hallmark of SDS, was not observed in this model. 18 Neither was leukemic transformation seen, though longer follow up of the animals than the reported four months may be required in order to observe such phenotypes. Interestingly, Raaijmakers et al showed previously that deletion of Sbds in osteoprogenitors, cells that form the niche for HSCs, induces bone marrow dysfunction with myelodysplasia in mice.…”

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confidence: 99%

“…Sbds deficiency does alter translation and ribosome biogenesis-related gene sets in MC-MMs. 18 This suggests that ribosome function in these cells could be altered, and that translation of factors essential for myelocyte differentiation could potentially be impaired. The mouse model described by Zambetti et al will allow these mechanistic aspects to be investigated in more detail, which over the longer term could result in the development of targeted therapies that can correct the morbidity and mortality due to SDS-associated neutropenia.…”

mentioning

confidence: 99%

“…17 In this issue, Raaijmakers and his team describe an elegant novel mouse model for SDS. 18 They made use of conditional Sbds knock-out mice and crossed them to mice expressing the CRE recombinase in Cebpa positive cells, with the aim of inactivating Sbds in a subset of HSCs. Whereas deficiency of Sbds in all Cepba-expressing tissues turned out to be lethal, embryos with Sbds deficiency in Cepba-positive cells were healthy at gestational age and showed normal fetal liver architecture.…”

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confidence: 99%

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A novel mouse model provides insights into the neutropenia associated with the ribosomopathy Shwachman-Diamond syndrome

Keersmaecker

2015

Haematologica

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Deficiency of the ribosome biogenesis gene Sbds in hematopoietic stem and progenitor cells causes neutropenia in mice by attenuating lineage progression in myelocytes

Cited by 52 publications

References 50 publications

The microenvironment in myelodysplastic syndromes: Niche-mediated disease initiation and progression

The microenvironment in myelodysplastic syndromes: Niche-mediated disease initiation and progression

Bcl‐2 proteins in development, health, and disease of the hematopoietic system

A novel mouse model provides insights into the neutropenia associated with the ribosomopathy Shwachman-Diamond syndrome

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