Constitutive Activation of the Canonical NF-κB Pathway Leads to Bone Marrow Failure and Induction of Erythroid Signature in Hematopoietic Stem Cells

Bone marrow failure (BMF), the inability to regenerate the differentiated cells of the blood, has a number of genetic and environmental etiologies, such as mutation of telomere-associated protein genes and immune-related aplastic anemia. Recently, mutations in DNA methyltransferase 3A (DNMT3A) have been found to be associated with approximately 15% of cases of primary myelofibrosis (MF), which can be a cause of BMF. The role of DNMT3A more broadly in hematopoiesis, and specifically in BMF, is currently poorly understood. DNMT3A is one of two de novo DNA methylation enzymes important in developmental fate choice. We showed that Dnmt3a is critical for normal murine hematopoiesis, as hematopoietic stem cells (HSCs) from Dnmt3a knockout (KO) mice displayed greatly diminished differentiation potential while their self-renewal ability was markedly increased1, in effect, leading to failure of blood regeneration or BMF. Combined with loss of Dnmt3b, HSCs exhibited a profound differentiation block, mediated in part by an increase of stabilized b-catenin. While we did not initially observe bone marrow pathology or malignancy development in mice transplanted with Dnmt3a KO HSCs, when we aged a large cohort of mice, all mice succumbed to hematologic disease within about 400 days. Roughly one-third of mice developed frank leukemia (acute lymphocytic leukemia or acute myeloid leukemia), one-third developed MDS, and the remainder developed primary myelofibrosis or chronic myelomonocytic leukemia. The pathological characteristics of the mice broadly mirror those of patients, suggesting the Dnmt3a KO mice can serve as a model for human DNMT3A-mutation associated disease. Strikingly, bone marrow of mice with different disease types exhibit distinct DNA methylation features. These will findings and the implications for disease development will be discussed. We are currently investigating the factors that drive different outcomes in the mice, including stressors such as exposure to interferons. We have hypothesized that HSC proliferation accelerates the Dnnmt3a-associated disease phenotypes. We have previously shown that interferons directly impinge on HSCs in the context of infections. Interferons activate HSCs to divide, generating differentiated progeny and cycling HSCs. Repeated interferon stimulation may permanently impair HSC function and bias stem cell output. When combined with loss of Dnmt3a, interferons may promote BMF. We will discuss broadly how external factors such as aging and infection may collaborate with specific genetic determinants to affect long-term hematopoiesis and malignancy development. Reference: Challen GA, Sun D, Jeong M, et al. Dnmt3a is essential for hematopoietic stem cell differentiation. Nat Genet 2012; 44: 23-31 Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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Cellular and molecular architecture of hematopoietic stem cells and progenitors in genetic models of bone marrow failure

JCI Insight ◽

10.1172/jci.insight.131018 ◽

2020 ◽

Vol 5 (4) ◽

Cited By ~ 1

Author(s):

Stephanie Heidemann ◽

Brian Bursic ◽

Sasan Zandi ◽

Hongbing Li ◽

Sagi Abelson ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Hematopoietic Stem Cells ◽

Bone Marrow Failure ◽

Genetic Models ◽

Molecular Architecture ◽

Hematopoietic Stem

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Generation of Dyskeratosis Congenita-like Hematopoietic Stem Cells through the Stable Inhibition of DKC1

10.21203/rs.3.rs-26927/v3 ◽

2021 ◽

Author(s):

Carlos Carrascoso-Rubio ◽

Hidde A. Zittersteijn ◽

Laura Pintado-Berninches ◽

Beatriz Fernández-Varas ◽

M. Luz Lozano ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Hematopoietic Stem Cells ◽

Bone Marrow Failure ◽

Clinical Manifestations ◽

Dyskeratosis Congenita ◽

Bone Marrow Failure Syndrome ◽

Hematopoietic Stem ◽

Human Cd34 ◽

Cd34 Cells

Abstract Dyskeratosis congenita (DC) is a rare telomere biology disorder, which results in different clinical manifestations, including severe bone marrow failure. To date, the only curative treatment for bone marrow failure in DC patients is allogeneic hematopoietic stem cell transplantation. However due to the toxicity associated to this treatment, improved therapies are recommended for DC patients. Here we aimed at generating DC-like human hematopoietic stem cells in which the efficacy of innovative therapies could be investigated. Because X-linked DC is the most frequent form of the disease and is associated with an impaired expression of DKC1, we have generated DC-like hematopoietic stem cells based on the stable knock-down of DKC1 in human CD34 + cells with lentiviral vectors encoding for DKC1 short hairpin RNAs. At a molecular level, DKC1 -interfered CD34 + cells showed a decreased expression of TERC, as well as a diminished telomerase activity and increased DNA damage, cell senescence and apoptosis. Moreover, DKC1 -interfered human CD34 + cells showed defective clonogenic ability and were incapable of repopulating the hematopoiesis of immunodeficient NSG mice. The development of DC-like hematopoietic stem cells will facilitate the understanding of the molecular and cellular basis of this inherited bone marrow failure syndrome, and will serve as a platform to evaluate the efficacy of new hematopoietic therapies for DC.

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DNA Microarray Analysis of GPI-Negative Hematopoietic Stem Cells in Paroxysmal Nocturnal Hemoglobinuria Patients.

Blood ◽

10.1182/blood.v106.11.1048.1048 ◽

2005 ◽

Vol 106 (11) ◽

pp. 1048-1048

Author(s):

Kazuhiko Ikeda ◽

Tsutomu Shichishima ◽

Yoshihiro Yamashita ◽

Yukio Maruyama ◽

Hiroyuki Mano

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Stem Cell ◽

Hematopoietic Stem Cells ◽

Hematopoietic Stem Cell ◽

Paroxysmal Nocturnal Hemoglobinuria ◽

Bone Marrow Failure ◽

Data Set ◽

Hematopoietic Stem ◽

Pnh Clone

Abstract Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal hematological disorder which is manifested by complement-mediated hemolysis, venous thrombosis, and bone marrow failure. Deficiencies of glycosylphosphatidylinositol (GPI)-anchored proteins, due to mutations in the phosphatidylinositol glycan-class A (PIG-A) gene, contribute to complement-mediated hemolysis and affect all hematopoietic lineages in PNH. However, it is unclear how a PNH clone with a PIG-A gene mutation expands in bone marrow. Although some genes, including the Wilms’ tumor gene (Shichishima et al, Blood, 2002), the early growth response gene, anti-apoptosis genes, and the gene localized at breakpoints of chromosome 12, have been reported as candidate genes that may associate with proliferations of a GPI-negative PNH clone, previous studies were not intended for hematopoietic stem cell, indicating that the differences in gene expressions between GPI-negative PNH clones and GPI-positive cells from PNH patients remain unclear at the level of hematopoietic stem cell. To identify genes contributing to the expansion of a PNH clone, here we compared the gene expression profiles between GPI-negative and GPI-positive fractions among AC133-positive hematopoietic stem cells (HSCs). By using the FACSVantage (Becton Dickinson, San Jose, CA) cell sorting system, both of CD59+AC133+ and CD59− AC133+ cells were purified from bone marrow mononuclear cells obtained from 11 individuals with PNH. Total RNA was isolated from each specimen with the use of RNeasy Mini column (Qiagen, Valencia, CA). The mRNA fractions were amplified, and were used to generate biotin-labeled cDNAs by the Ovation Biotin system (NuGEN Technologies, San Carlos, CA). The resultant cDNAs were hybridized with a high-density oligonucleotide microarray (HGU133A; Affymetrix, Santa Clara, CA). A total of >22,000 probe sets (corresponding to >14,000 human genes) were assayed in each experiment, and thier expression intensities were analyzed by GeneSpring 7.0 software (Silicon Genetics, Redwood, CA). Comparison between CD59-negative and CD59-positive HSCs has identified a number of genes, expression level of which was statistically different (t-test, P <0.001) between the two fractions. Interestingly, one of the CD59− -specific genes isolated in our data set turned out to encode a key component of the proteasome complex. On the other hand, a set of transcriptional factors were specifically silenced in the CD59− HSCs. These data indicate that affected CD59-negative stem cells have a specific molecular signature which is distinct from that for the differentiation level-matched normal HSCs. Our data should pave a way toward the molecular understanding of PNH.

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Ott1(Rbm15)-Deficient Hematopoietic Stem Cells Are Unable to Maintain Quiescence During Replicative Stress and Display Features of Premature Aging,

Blood ◽

10.1182/blood.v118.21.3433.3433 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3433-3433

Author(s):

Nan Xiao ◽

Kaushal Jani ◽

Jonathan L Jesneck ◽

Glen D Raffel

Keyword(s):

Gene Expression ◽

Stem Cells ◽

Bone Marrow ◽

Steady State ◽

Hematopoietic Stem Cells ◽

Bone Marrow Failure ◽

Gene Set Enrichment Analysis ◽

Wild Type ◽

Hematopoietic Stem ◽

Replicative Stress

Abstract Abstract 3433 With age, hematopoietic stem cells (HSCs) have numerical expansion, skewing towards myeloid development, loss of lymphoid potential, an underlying pro-inflammatory state and loss of self-renewal potential thus severely limiting responses to hematopoietic stress, ultimately leading to bone marrow failure. The mechanisms and pathways responsible for these changes in aged HSCs are incompletely understood. Using a conditional allele of Ott1, a gene originally isolated as the 5' fusion partner in t(1;22) acute megakaryocytic leukemia, we previously found a global regulatory role for the gene in hematopoiesis. Deletion of Ott1 in adult mice utilizing Mx1-cre recapitulated certain aspects of aging hematopoiesis including increased Lin−Sca1+c-Kit+ (LSK) population, myeloid expansion and decreased lymphopoiesis. The LSK compartment was further characterized using SLAM and CD34/Flk2 markers and demonstrated normal levels of LT-HSCs and increased ST-HSCs. Despite sufficient LT-HSC numbers, Ott1-deleted bone marrow was unable to competitively or non-competitively repopulate irradiated recipients. To exclude a homing or engraftment effect, Ott1flox/null Mx1-cre bone marrow was transplanted with competitor then excised post-engraftment. The rapid loss of the Ott1-deficient graft demonstrated Ott1 is required for maintenance under competitive stress. In contrast, primary mice undergoing Ott1 excision lived a normal lifespan and were able to maintain sufficient hematopoiesis although with a partial reduction in bone marrow clonagenicity showing loss of Ott1 is not limiting under steady state conditions. To test the HSC requirement for Ott1 under replicative stress, Ott1 knockout mice were challenged with 5-fluorouracil (5-FU). Ott1-deleted mice treated with 5-FU displayed delayed peripheral blood neutrophil recovery and showed accelerated bone marrow failure. Cell cycle analysis of steady state Ott1 knockout HSCs showed a similar profile to wild type controls, however, after 5-FU treatment, the G0 fraction was dramatically reduced. The G0 fraction is associated with the quiescent, self-renewing HSC population, therefore, Ott1 is required for maintaining HSC quiescence during replicative stress but not steady state hematopoiesis. To more specifically assess whether the functional hematopoietic changes seen after loss of Ott1 were accompanied by alterations in known aging-associated pathways, Gene Set Enrichment Analysis comparing Ott1-deleted HSCs in steady state to aged HSCs was performed and showed a highly enriched gene expression signature (NES 2.02 p<0.0001). Physiologic sequelae of HSC aging were observed after Ott1 excision including activation of NFκβ, elevation of reactive oxygen species (ROS), increase in DNA damage (γH2A.X levels) and activation of p38Mapk. Although ROS was elevated under steady state conditions, neither apoptosis, senescence or proliferation was significantly different from wild type control HSCs. Furthermore, anti-oxidant treatment with N-acetyl-cysteine was unable to rescue the HSC maintenance defect of the Ott1 knockout, signifying additional requirements in HSCs for Ott1 beyond regulation of ROS. An observed increase of mitochondrial mass in Ott1-deleted HSCs suggests an upstream function for Ott1 in metabolic control, potentially contributing to ROS generation or degradation. In summary, we have demonstrated an essential role for Ott1 in maintaining HSC quiescence during replicative stress and shown loss of Ott1 leads to the acquisition of key gene expression patterns and pathophysiologic changes associated with aging. These data suggest Ott1 functions in part to oppose specific consequences of aging in the hematopoietic compartment. Ott1 and Ott1-dependent pathways therefore represent a potential therapeutic target to prevent the morbidity and mortality arising from age-related defects in hematopoiesis. Disclosures: No relevant conflicts of interest to declare.

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ALDH2 Polymorphism In Japanese Children With Acquired Aplastic Anemia

Blood ◽

10.1182/blood.v122.21.3717.3717 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3717-3717

Author(s):

Nozomu Kawashima ◽

Atsushi Narita ◽

Xinan Wang ◽

Yinyan Xu ◽

Hirotoshi Sakaguchi ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Hematopoietic Stem Cells ◽

Aplastic Anemia ◽

Categorical Data ◽

Japanese Population ◽

Bone Marrow Failure ◽

Japanese Children ◽

Hematopoietic Stem ◽

Variant Alleles

Abstract Introduction Aplastic anemia is a syndrome of bone marrow failure (BMF) characterized by peripheral pancytopenia and marrow hypoplasia. Injury to hematopoietic cells, such as immune-mediated cytotoxicity, can cause aplastic anemia; the successful treatment of aplastic anemia using immunosuppressive therapy supports this hypothesis. Another proposed mechanism is an intrinsic defect of hematopoietic stem cells, which is the presumed major cause of congenital BMF, but this mechanism has not been definitively established in patients with acquired aplastic anemia. Aldehyde dehydrogenase 2 (ALDH2) deficiency resulting from a Glu504Lys substitution (A allele) is prevalent in the Japanese population: the A allele frequency is nearly 50% in the Japanese population. AA homozygotes show scarce catalysis of aldehydes, and GA heterozygotes display strongly reduced catalysis when compared with GG homozygotes. In patients with Fanconi anemia (FA), the most frequent inherited cause of BMF, progression of BMF was strongly accelerated in carriers of the GA and AA allele, possibly due to endogenous DNA damage caused by aldehydes that could not otherwise be repaired through the FA pathway. We studied the role of ALDH2 polymorphism in Japanese children with acquired aplastic anemia. Patients and Methods Seventy-nine Japanese children younger than 15 years who were referred to the Japanese Red Cross Nagoya First Hospital and Nagoya University Hospital were included in this study. Patients were excluded if they had paroxysmal nocturnal hemoglobinuria, toxic exposure to chemicals, or a clinical diagnosis of congenital BMF. Disease severity was classified based on the criteria of the International Aplastic Anemia Study Group as very severe (n = 10), severe (n = 41) and non-severe (n = 28). ALDH2 Glu487Lys polymorphisms (rs671) and alcohol dehydrogenases 1B (ADH1B) Arg47His polymorphisms (rs1229984) were genotyped with site-specific polymerase chain reaction with confronting two-pair primers. Statistical analysis was performed by Fisher’s exact test for categorical data and by Mann-Whitney U test for non-categorical data. P<0.05 was considered to indicate statistical significance. Results Forty children were genotyped with GG, 29 children with GA, and 10 children with AA. The distribution of the ALDH2 variant alleles in children with acquired aplastic anemia was not significantly different from the reported allele frequencies in the healthy Japanese population (GG = 1141, GA = 941, AA = 217; P = 0.4). However, age at diagnosis was significantly lower in children harboring AA (median 2 years, range 0.83-6 years) when compared with children harboring GG (median 10 years, range 1.6-16 years) and GA (median 10 years, range 1-14 years), respectively (P <0.01). In contrast, other clinical characteristics, including duration of disease onset to disease diagnosis, severity of the disease, and peripheral blood cell counts, were not significantly different among the ALDH2 groups. ADH1B may influence the concentration of aldehydes by catalyzing aliphatic alcohol. The ADH1B polymorphism (A allele) confers substantially higher enzymatic activity than the less active form (G allele), which is prevalent in Japanese, and thus may involve aldehyde toxicity. The distribution of the ADH1B variant alleles was not significantly different from the reported allele frequencies in the healthy Japanese population, and age at diagnosis of aplastic anemia was not significantly different among ADH1B variant allele groups in our cohort. Discussion ALDH2 catalyzes acetaldehyde as well as formaldehyde and other aldehydes, which can be genotoxic via DNA-protein crosslinking. Given that our cohort includes only children (alcohol intake is not a factor), intrinsic aldehydes that are mostly produced during lipid oxidation may damage hematopoietic stem cells, resulting in bone marrow failure. In conclusion, endogenous aldehydes may damage hematopoietic cells, resulting in early onset of disease in children with acquired aplastic anemia as well as in patients with FA. Disclosures: No relevant conflicts of interest to declare.

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Senescence of Hematopoietic Stem Cells and Bone Marrow Failure

International Journal of Hematology ◽

10.1532/ijh97.05094 ◽

2005 ◽

Vol 82 (3) ◽

pp. 190-195 ◽

Cited By ~ 8

Author(s):

Jichun Chen

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Hematopoietic Stem Cells ◽

Bone Marrow Failure ◽

Hematopoietic Stem

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Impaired Osteoblastic Differentiation of MSCs Suppresses Normal Hematopoiesis in MDS

Blood ◽

10.1182/blood-2020-142284 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 17-18

Author(s):

Yasutaka Hayashi ◽

Kimihito Cojin Kawabata ◽

Yosuke Tanaka ◽

Yasufumi Uehara ◽

Shigeru Kiryu ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Bone Formation ◽

Hematopoietic Stem Cells ◽

Trabecular Bone ◽

Bone Marrow Failure ◽

Bone Volume ◽

Marker Genes ◽

Double Labeling ◽

Hematopoietic Stem

Myelodysplastic syndromes (MDS) is a clonal disorder of hematopoietic stem cells (HSCs) characterized by clonal hematopoietic stem cells (HSCs) with cytopenia, morphological abnormalities, genetic alteration, ineffective normal hematopoiesis, and frequent progression to AML. It has long remained unresolved how MDS cells, which are less proliferative, inhibit normal hematopoiesis and eventually come to dominate the bone marrow space. Despite several studies of mesenchymal stem cells (MSCs), one of the principal components of HSC niche supporting normal hematopoiesis, the molecular mechanisms underlying this process remain unclear. In this study, we examined the mechanism by which less-proliferative MDS cells outcompete normal hematopoiesis through the effects on MSCs using serially transplantable Abcg2-induced MDS/AML model we recently generated. The recipient-derived normal BM cells displayed a considerably lower colony output with markedly decreased numbers of the hematopoietic stem progenitor cells (HSPCs) . However, there were no direct effects on the colony-forming ability of the recipient HSPCs co-cultured with MDS/AML cells, indicating that MDS/AML cells inhibited hematopoiesis through alteration of bone marrow microenvironment, such as MSCs, rather than direct interaction between normal and malignant HSCs. We next analyzed histological features of BM specimens. Interestingly, bone sections from the MDS/AML mice showed a reduced trabecular bone and narrowed growth plates. Moreover, micro computed tomography (micro-CT) analysis of the femora showed a significant reduction of the trabecular bone volume in the recipient mice transplanted with the MDS/AML BM cells. We detected decreased bone formation based on the calcein double labeling, but unchanged numbers of the TRAP-positive mononuclear or multinucleated (osteoclastic) cells in the MDS/AML samples, suggesting that the reduced bone volume was caused by suppressed bone formation. The impaired bone formation was also observed in the human MDS patients in terms of lower bone volume and decreased expression of BGLAP, one of osteogenic markers. In line with the above findings, single cell qRT-PCR analyses of mouse MSCs displayed downregulation of a line of osteolineage markers, indicating that MDS/AML cells suppress bone formation through inhibiting osteolineage differentiation of MSCs. Based on the findings, we next examined if re-induction of osteolineage differentiation of the MDS/AML-derived MSCs could rescue the potential of MSCs to support normal hematopoiesis. Importantly, the number of colony-forming cells (CFCs) was significantly restored by inducing differentiation of MDS/AML-derived MSCs toward osteogenic lineage both in vitro and in vivo. These results indicate that the impairment of osteolineage differentiation is the principal cause for an impaired normal hematopoiesis in MDS/AML, and that restoring the supportive niche will be a potential therapeutic option. Since extracellular vesicles (EVs) derived from MDS/AML cells are critical mediators of intercellular communication, we examined the molecular mechanism underlying the dysfunction of MSCs via EVs. As expected, EVs from MDS/AML cells were incorporated into the normal MSCs where osteolineage marker genes were clearly downregulated, and the number of CFCs significantly decreased in the HSPCs co-cultured with MSCs treated by the MDS/AML-derived EVs. Moreover, by comprehensively analyzing microRNAs (miRNAs) enriched in EVs derived from MDS/AML cells, we identified several miRNAs that impaired the differentiation of normal MSCs. These results suggested that miRNAs in EVs derived from MDS/AML cells disrupted the hematopoietic supporting niche through suppressing an osteolineage differentiation of MSCs. Here we uncover a heretofore unrecognized mechanism of bone marrow failure in MDS via the impairment of osteolineage differentiation in MSCs. EVs from MDS cells will be an attractive therapeutic target to restore the supportive niches, such as MSCs, for the remaining normal HSCs. Figure Disclosures No relevant conflicts of interest to declare.

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Id2 Is Required for the Self-Renewal and Proliferation of Hematopoietic Stem Cells

Blood ◽

10.1182/blood.v126.23.1173.1173 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1173-1173 ◽

Cited By ~ 1

Author(s):

Lei Sun

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Hematopoietic Stem Cells ◽

Cell Biology ◽

Conflicts Of Interest ◽

Bone Marrow Failure ◽

Conditional Knockout ◽

The Self ◽

Self Renewal ◽

Hematopoietic Stem

Abstract The production of mammalian blood cells is sustained throughout life by the self-renewal and differentiation of hematopoietic stem cells (HSCs). Dysregulation in this system leads to different pathologies including anemia, bone marrow failure and hematopoietic malignancies. The Helix-Loop-Helix transcriptional regulator Id2 plays essential roles in regulating proliferation and cell fate of hematopoietic progenitors; however, its role in regulating HSC development remains largely unknown. To assess the function of Id2 in HSCs, we developed two mouse models, including an Id2 conditional knockout model and an Id2-EYFP model, in which EYFP expression is driven by endogenous Id2 promoter. When we examined HSC function by serial transplantation, we found that mice transplanted with Id2F/F Mx1-Cre+ conditionally deleted bone marrow cells became moribund more rapidly after primary and secondary transplantation, compared to those transplanted with Id2+/F Mx1-Cre+ bone marrow, suggesting that HSC self-renewal is impaired when Id2 is deleted. To further determine if self-renewal and maintenance of HSCs depends on the expression level of Id2, we purified HSCs with different levels of Id2 expression using Id2-EYFP mice to specifically address the role of Id2 in HSCs. First, we confirmed Id2 is highly expressed in HSCs in this model. Second, when HSCs with either low or high levels of Id2-EYFP were transplanted into irradiated mice, cells with high levels of Id2 reconstituted transplanted recipients faster than those with low levels of Id2 at 3 weeks and longer, suggesting that Id2 expression is associated with repopulation advantage. Furthermore, Ki-67 staining showed that HSCs with high levels of Id2 have 15-fold more cells in G2/M phase, and fewer cells in G0. BrdU staining also suggested that there are 5-fold more BrdU+ cells in HSCs with high levels of Id2, indicating that Id2 expression correlates with cell cycle progression in HSCs. In addition, p57 has been reported to be required for quiescence of HSCs. Our preliminary data showed that p57 is downregulated in HSCs with high levels of Id2, and p57 is correspondingly upregulated in Id2-null HSCs. Altogether, our data demonstrate that Id2 is required for the self-renewal and proliferation of HSCs, and suggest a link between Id2 and the transcriptional regulatory networks that regulate the functional hematopoietic system. Since Id2 is also expressed in other adult stem cells including muscle and neuronal stem cells, as well as cancer cells, we believe our results can improve our understanding of stem cell biology and cancer development, and contribute to the identification of novel molecules that may be targeted to eliminate cancer stem cells. Disclosures No relevant conflicts of interest to declare.

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Profilin 1 is essential for retention and metabolism of mouse hematopoietic stem cells in bone marrow

Blood ◽

10.1182/blood-2013-04-498469 ◽

2014 ◽

Vol 123 (7) ◽

pp. 992-1001 ◽

Cited By ~ 27

Author(s):

Junke Zheng ◽

Zhigang Lu ◽

Fatih Kocabas ◽

Ralph T. Böttcher ◽

Mercedes Costell ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Stem Cell ◽

Hematopoietic Stem Cells ◽

Bone Marrow Failure ◽

Metabolic Switch ◽

Cell Retention ◽

Hematopoietic Stem ◽

Key Points

Key Points The deletion of pfn1 led to bone marrow failure, loss of quiescence, increased apoptosis and mobilization, and a metabolic switch of HSCs. Pfn1 partially acts through the axis of pfn1/Gα13/EGR1 to regulate stem cell retention and metabolism in the bone marrow.

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