Prdm16 is a physiologic regulator of hematopoietic stem cells

Aguiló, Francesca; Avagyan, Serine; Labar, Amy S.; Sevilla, Ana; Lee, Dung‐Fang; Kumar, Pravin; Lemischka, Ihor R.; Zhou, Betty Y.; Snoeck, Hans-Willem

doi:10.1182/blood-2010-08-300145

Cited by 129 publications

(144 citation statements)

References 53 publications

(105 reference statements)

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“…Dysregulation of MAPK signalling has been linked to obesity and diabetes and plays a role in insulin signalling [43]. Additionally, PRDM16, a transcription cofactor with an important role in the development of brown adipose tissue in mice [31] and later identified as important for establishment and maintenance of the haematopoietic stem cell pool balance through the regulation of genes and transcription regulators [44] and by regulating reactive oxygen species levels (ROS) [32], was identified as both a DMR and a differentially methylated locus in IUGR. This finding strongly suggests that the epigenetic regulation of PRDM16 may play a role in IUGRassociated metabolic disease susceptibility, including alteration of stem cell populations in multiple organs as well as the level of ROS, known to be elevated in metabolic disease.…”

Section: Discussionmentioning

confidence: 99%

DNA hypermethylation of CD3+ T cells from cord blood of infants exposed to intrauterine growth restriction

et al. 2016

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Aims/hypothesis Intrauterine growth restriction (IUGR) is associated with increased susceptibility to obesity, metabolic syndrome and type 2 diabetes. Although the mechanisms underlying the developmental origins of metabolic disease are poorly understood, evidence suggests that epigenomic alterations play a critical role. We sought to identify changes in DNA methylation patterns that are associated with IUGR in CD3 + T cells purified from umbilical cord blood obtained from male newborns who were appropriate for gestational age (AGA) or who had been exposed to IUGR. Methods CD3 + T cells were isolated from cord blood obtained from IUGR and AGA infants. The genome-wide methylation profile in eight AGA and seven IUGR samples was determined using the HELP tagging assay. Validation analysis using targeted bisulfite sequencing and bisulfite massARRAY was performed on the original cohort as well as biological replicates consisting of two AGA and four IUGR infants. The Segway algorithm was used to identify methylation changes within regulatory regions of the genome. Results A global shift towards hypermethylation in IUGR was seen compared with AGA (89.8% of 4,425 differentially methylated loci), targeted to regulatory regions of the genome, specifically promoters and enhancers. Pathway analysis identified dysregulation of pathways involved in metabolic disease (type 2 diabetes mellitus, insulin signalling, mitogen-activated protein kinase signalling) and T cell development, regulation and activation (T cell receptor signalling), as well as transcription factors (TCF3, LEF1 and NFATC) that regulate T cells. Furthermore, bump-hunting analysis revealed differentially methylated regions in PRDM16 and HLA-DPB1, genes important for adipose tissue differentiation, stem cell maintenance and function and T cell activation. Conclusions/interpretation Our findings suggest that the alterations in methylation patterns observed in IUGR CD3 + T cells may have functional consequences in targeted genes, regulatory regions and transcription factors. These may serve as biomarkers to identify those at 'high risk' for diminished attainment of full health potential who can benefit from early interventions.

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Section: Discussionmentioning

confidence: 99%

DNA hypermethylation of CD3+ T cells from cord blood of infants exposed to intrauterine growth restriction

et al. 2016

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“…For the detection of long-term hematopoietic stem cells (LT-HSC), shortterm HSC (ST-HSC), and multipotent progenitors (MPP) (27,28), splenocytes or bone marrow cells were incubated with biotinylated Lin markerspecific Abs (except anti-CD127), then with streptavidin-PerCP, and finally with fluorescently labeled Abs to CD117, Sca-1, CD150, and CD135.…”

Section: Flow Cytometry Analyses and Cell Sortingmentioning

confidence: 99%

Mast Cell–deficient KitW-sh “Sash” Mutant Mice Display Aberrant Myelopoiesis Leading to the Accumulation of Splenocytes That Act as Myeloid-Derived Suppressor Cells

Michel

Schüler

Friedrich

et al. 2013

The Journal of Immunology

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Mast cell-deficient KitW-sh “sash” mice are widely used to investigate mast cell functions. However, mutations of c-Kit also affect additional cells of hematopoietic and nonimmune origin. In this study, we demonstrate that KitW-sh causes aberrant extramedullary myelopoiesis characterized by the expansion of immature lineage-negative cells, common myeloid progenitors, and granulocyte/macrophage progenitors in the spleen. A consistent feature shared by these cell types is the reduced expression of c-Kit. Populations expressing intermediate and high levels of Ly6G, a component of the myeloid differentiation Ag Gr-1, are also highly expanded in the spleen of sash mice. These cells are able to suppress T cell responses in vitro and phenotypically and functionally resemble myeloid-derived suppressor cells (MDSC). MDSC typically accumulate in tumor-bearing hosts and are able to dampen immune responses. Consequently, transfer of MDSC from naive sash mice into line 1 alveolar cell carcinoma tumor-bearing wild-type littermates leads to enhanced tumor progression. However, although it can also be observed in sash mice, accelerated growth of transplanted line 1 alveolar cell carcinoma tumors is a mast cell–independent phenomenon. Thus, the KitW-sh mutation broadly affects key steps in myelopoiesis that may have an impact on mast cell research.

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“…Given the critical role of Evi1 and Prdm16 to maintain HSCs, 5,6 the low expression of MPO probably indicates the undifferentiated stem cell-like properties of these types of leukemia. Eveillard et al also showed that rearrangements of these genes are associated with inferior survival, and are frequently found in patients with secondary AML.…”

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confidence: 99%

The subtype-specific features of EVI1 and PRDM16 in acute myeloid leukemia

et al. 2015

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We read with interest the response "The closely related rare and severe acute myeloid leukemias carrying EVI1 or PRDM16 mutations share singular biological features" by Eveillard et al. 1 to our recent publication.2 EVI1 and PRDM16 belong to the Prdm family, which is characterized by an N-terminal PR domain with multiple zinc fingers. Prdm family members control gene expression through modification of the chromatin state. It has been shown that EVI1 and PRDM16 have similar functions in normal and malignant hematopoiesis.3,4 They both cause acute myeloid leukemia (AML), and loss of either leads to severe defects of hematopoietic stem cell (HSC) activity. Here, we would like to clarify similarities and differences of EVI1 and PRDM16 as poor prognosis biomarkers in AML.Eveillard et al. provide evidence that EVI1-and PRDM16-rearranged AML share many features including micromegakaryocytes, multilineage dysplasia, and low myeloperoxidase (MPO)-expressing blasts. Given the critical role of Evi1 and Prdm16 to maintain HSCs, 5,6 the low expression of MPO probably indicates the undifferentiated stem cell-like properties of these types of leukemia. Eveillard et al. also showed that rearrangements of these genes are associated with inferior survival, and are frequently found in patients with secondary AML. These findings, together with those in previous reports, 3,4 suggest that both EVI1 and PRDM16 are activated by chromosomal rearrangements, confer a poor prognosis presumably by promoting stem cell program in leukemia cells, and are involved in the development of secondary AML. It should be noted, however, that another study found only EVI1-rearrangement is associated with monosomy 7, while PRDM16-rearrangement had no preferential association with other cytogenetic abnormalities.7 Therefore, there may be some mechanistic differences between EVI1-and PRDM16-induced leukemogenesis. In addition, whether high expressions of EVI1 and PRDM16 are independent prognostic factors even in secondary AML remains to be elucidated.High expressions of EVI1 and PRDM16 are also found in a subgroup of AML patients without translocations of these gene loci. We and others have previously shown that EVI1 is a poor prognostic factor in MLL-rearranged AML. (Figure 1). Furthermore, a very recent report showed the mutually exclusive expression of EVI1 and PRDM16 in AMLs without obvious translocation.10 High EVI1 expression was mainly detected in MLL-rearranged AML and megakaryocytic-lineage AML, while high PRDM16 expression was detected in myelocytic-lineage AML and myelomonocyticlineage AML without MLL-rearrangements. Thus, it appears that PRDM16 is up-regulated through different mechanisms from those for EVI1 in AML patients. Further investigation is necessary to understand how these Prdm factors are activated in specific types of AML, and to elucidate their subtype-specific roles in AML development.

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Prdm16 is a physiologic regulator of hematopoietic stem cells

Cited by 129 publications

References 53 publications

DNA hypermethylation of CD3+ T cells from cord blood of infants exposed to intrauterine growth restriction

DNA hypermethylation of CD3+ T cells from cord blood of infants exposed to intrauterine growth restriction

Mast Cell–deficient KitW-sh “Sash” Mutant Mice Display Aberrant Myelopoiesis Leading to the Accumulation of Splenocytes That Act as Myeloid-Derived Suppressor Cells

The subtype-specific features of EVI1 and PRDM16 in acute myeloid leukemia

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