scholarly journals Loss of tRNA-modifying enzyme Elp3 activates a p53-dependent antitumor checkpoint in hematopoiesis

2021 ◽  
Vol 218 (3) ◽  
Author(s):  
Adeline Rosu ◽  
Najla El Hachem ◽  
Francesca Rapino ◽  
Kevin Rouault-Pierre ◽  
Joseph Jorssen ◽  
...  
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Bone Marrow Failure ◽  
Amino Acid Deprivation ◽  
Hematopoietic Stem ◽  
Hematopoietic System ◽  
Transfer Rnas ◽  
Translational Machinery ◽  
Highly Sensitive

The hematopoietic system is highly sensitive to perturbations in the translational machinery, of which an emerging level of regulation lies in the epitranscriptomic modification of transfer RNAs (tRNAs). Here, we interrogate the role of tRNA anticodon modifications in hematopoiesis by using mouse models of conditional inactivation of Elp3, the catalytic subunit of Elongator that modifies wobble uridine in specific tRNAs. Loss of Elp3 causes bone marrow failure by inducing death in committing progenitors and compromises the grafting activity of hematopoietic stem cells. Mechanistically, Elp3 deficiency activates a p53-dependent checkpoint in what resembles a misguided amino acid deprivation response that is accompanied by Atf4 overactivation and increased protein synthesis. While deletion of p53 rescues hematopoiesis, loss of Elp3 prompts the development of p53-mutated leukemia/lymphoma, and inactivation of p53 and Elongator cooperatively promotes tumorigenesis. Specific tRNA-modifying enzymes thus condition differentiation and antitumor fate decisions in hematopoietic stem cells and progenitors.

scholarly journals Prdm16 is a physiologic regulator of hematopoietic stem cells

Blood ◽  
2011 ◽  
Vol 117 (19) ◽  
pp. 5057-5066 ◽  
Author(s):  
Francesca Aguilo ◽  
Serine Avagyan ◽  
Amy Labar ◽  
Ana Sevilla ◽  
Dung-Fang Lee ◽  
...  
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Fetal Liver ◽  
Feedback Loops ◽  
Hematopoietic Stem ◽  
Hematopoietic System ◽  
Number Of Genes ◽  
Adult Bone ◽  
Deficient Mice

Abstract Fetal liver and adult bone marrow hematopoietic stem cells (HSCs) renew or differentiate into committed progenitors to generate all blood cells. PRDM16 is involved in human leukemic translocations and is expressed highly in some karyotypically normal acute myeloblastic leukemias. As many genes involved in leukemogenic fusions play a role in normal hematopoiesis, we analyzed the role of Prdm16 in the biology of HSCs using Prdm16-deficient mice. We show here that, within the hematopoietic system, Prdm16 is expressed very selectively in the earliest stem and progenitor compartments, and, consistent with this expression pattern, is critical for the establishment and maintenance of the HSC pool during development and after transplantation. Prdm16 deletion enhances apoptosis and cycling of HSCs. Expression analysis revealed that Prdm16 regulates a remarkable number of genes that, based on knockout models, both enhance and suppress HSC function, and affect quiescence, cell cycling, renewal, differentiation, and apoptosis to various extents. These data suggest that Prdm16 may be a critical node in a network that contains negative and positive feedback loops and integrates HSC renewal, quiescence, apoptosis, and differentiation.

scholarly journals Mitochondria in the maintenance of hematopoietic stem cells: new perspectives and opportunities

Blood ◽  
2019 ◽  
Vol 133 (18) ◽  
pp. 1943-1952 ◽  
Author(s):  
Marie-Dominique Filippi ◽  
Saghi Ghaffari
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Blood Cells ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Hematopoietic System ◽  
Cellular Energy ◽  
Cell Pool ◽  
Stem Cell Pool

Abstract The hematopoietic system produces new blood cells throughout life. Mature blood cells all derived from a pool of rare long-lived hematopoietic stem cells (HSCs) that are mostly quiescent but occasionally divide and self-renew to maintain the stem cell pool and to insure the continuous replenishment of blood cells. Mitochondria have recently emerged as critical not only for HSC differentiation and commitment but also for HSC homeostasis. Mitochondria are dynamic organelles that orchestrate a number of fundamental metabolic and signaling processes, producing most of the cellular energy via oxidative phosphorylation. HSCs have a relatively high amount of mitochondria that are mostly inactive. Here, we review recent advances in our understanding of the role of mitochondria in HSC homeostasis and discuss, among other topics, how mitochondrial dynamism and quality control might be implicated in HSC fate, self-renewal, and regenerative potential.

scholarly journals Autophagy is dispensable for the maintenance of hematopoietic stem cells in neonates

2021 ◽  
Vol 5 (6) ◽  
pp. 1594-1604
Author(s):  
Michihiro Hashimoto ◽  
Terumasa Umemoto ◽  
Ayako Nakamura-Ishizu ◽  
Takayoshi Matsumura ◽  
Tomomasa Yokomizo ◽  
...  
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Cell Function ◽  
Bone Marrow Failure ◽  
Mitochondrial Metabolism ◽  
Conditional Knockout ◽  
Mitochondrial Activity ◽  
Hematopoietic Stem ◽  
Neonatal Stage

Abstract Hematopoietic stem cells (HSCs) undergo self-renewal or differentiation to sustain lifelong hematopoiesis. HSCs are preserved in quiescence with low mitochondrial activity. Recent studies indicate that autophagy contributes to HSC quiescence through suppressing mitochondrial metabolism. However, it remains unclear whether autophagy is involved in the regulation of neonatal HSCs, which proliferate actively. In this study, we clarified the role of autophagy in neonatal HSCs using 2 types of autophagy-related gene 7 (Atg7)-conditional knockout mice: Mx1-Cre inducible system and Vav-Cre system. Atg7-deficient HSCs exhibited excess cell divisions with enhanced mitochondrial metabolism, leading to bone marrow failure at adult stage. However, Atg7 deficiency minimally affected hematopoiesis and metabolic state in HSCs at neonatal stage. In addition, Atg7-deficient neonatal HSCs exhibited long-term reconstructing activity, equivalent to wild-type neonatal HSCs. Taken together, autophagy is dispensable for stem cell function and hematopoietic homeostasis in neonates and provide a novel aspect into the role of autophagy in the HSC regulation.

scholarly journals The role of apoptosis in the development of AGM hematopoietic stem cells revealed by Bcl-2 overexpression

Blood ◽  
2004 ◽  
Vol 103 (11) ◽  
pp. 4084-4092 ◽  
Author(s):  
Claudia Orelio ◽  
Kirsty N. Harvey ◽  
Colin Miles ◽  
Robert A. J. Oostendorp ◽  
Karin van der Horn ◽  
...  
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Fetal Liver ◽  
Regulatory Elements ◽  
Hematopoietic Stem ◽  
Hematopoietic System ◽  
Transcriptional Regulatory Elements ◽  
Tissue Region

Abstract Apoptosis is an essential process in embryonic tissue remodeling and adult tissue homeostasis. Within the adult hematopoietic system, it allows for tight regulation of hematopoietic cell subsets. Previously, it was shown that B-cell leukemia 2 (Bcl-2) overexpression in the adult increases the viability and activity of hematopoietic cells under normal and/or stressful conditions. However, a role for apoptosis in the embryonic hematopoietic system has not yet been established. Since the first hematopoietic stem cells (HSCs) are generated within the aortagonad-mesonephros (AGM; an actively remodeling tissue) region beginning at embryonic day 10.5, we examined this tissue for expression of apoptosis-related genes and ongoing apoptosis. Here, we show expression of several proapoptotic and antiapoptotic genes in the AGM. We also generated transgenic mice overexpressing Bcl-2 under the control of the transcriptional regulatory elements of the HSC marker stem cell antigen-1 (Sca-1), to test for the role of cell survival in the regulation of AGM HSCs. We provide evidence for increased numbers and viability of Sca-1+ cells in the AGM and subdissected midgestation aortas, the site where HSCs are localized. Most important, our in vivo transplantation data show that Bcl-2 overexpression increases AGM and fetal liver HSC activity, strongly suggesting that apoptosis plays a role in HSC development.

The role of children's bone marrow mesenchymal stromal cells in the ex vivo expansion of autologous and allogeneic hematopoietic stem cells

2015 ◽  
Vol 39 (10) ◽  
pp. 1099-1110 ◽  
Author(s):  
Iordanis Pelagiadis ◽  
Eftichia Stiakaki ◽  
Christianna Choulaki ◽  
Maria Kalmanti ◽  
Helen Dimitriou
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Hematopoietic Stem Cells ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Ex Vivo ◽  
Ex Vivo Expansion ◽  
Hematopoietic Stem

scholarly journals The Dynamic Interface Between the Bone Marrow Vascular Niche and Hematopoietic Stem Cells in Myeloid Malignancy

2021 ◽  
Vol 9 ◽  
Author(s):  
Laura Mosteo ◽  
Joanna Storer ◽  
Kiran Batta ◽  
Emma J. Searle ◽  
Delfim Duarte ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Hematopoietic Stem Cells ◽  
Hematopoietic Stem ◽  
Vascular Niche ◽  
Dynamic Interface ◽  
Bone Marrow Vascular Niche ◽  
Bidirectional Interactions ◽  
Vascular Compartment

Hematopoietic stem cells interact with bone marrow niches, including highly specialized blood vessels. Recent studies have revealed the phenotypic and functional heterogeneity of bone marrow endothelial cells. This has facilitated the analysis of the vascular microenvironment in steady state and malignant hematopoiesis. In this review, we provide an overview of the bone marrow microenvironment, focusing on refined analyses of the marrow vascular compartment performed in mouse studies. We also discuss the emerging role of the vascular niche in “inflamm-aging” and clonal hematopoiesis, and how the endothelial microenvironment influences, supports and interacts with hematopoietic cells in acute myeloid leukemia and myelodysplastic syndromes, as exemplar states of malignant myelopoiesis. Finally, we provide an overview of strategies for modulating these bidirectional interactions to therapeutic effect in myeloid malignancies.

scholarly journals Accessibility Over Transposable Elements Reveals Genetic Determinants of Stemness Properties in Normal and Leukemic Hematopoiesis

2021 ◽  
Author(s):  
Bettina Nadorp ◽  
Giacomo Grillo ◽  
Aditi Qamra ◽  
Amanda Mitchell ◽  
Christopher Arlidge ◽  
...  
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Chromatin Accessibility ◽  
Genetic Determinants ◽  
Hematopoietic Stem ◽  
Transcription Regulators ◽  
Docking Sites ◽  
Cellular Hierarchy ◽  
Mutational Processes

AbstractDespite most acute myeloid leukemia (AML) patients achieving complete remission after induction chemotherapy, two thirds of patients will relapse with fatal disease within 5 years. AML is organized as a cellular hierarchy sustained by leukemia stem cells (LSC) at the apex, with LSC properties directly linked to tumor progression, therapy failure and disease relapse 1–5. Despite the central role of LSC in poor patient outcomes, little is known of the genetic determinants of their stemness properties 6–8. Although much AML research focuses on mutational processes and their impact on gene expression programs, the genetic determinants of cell state properties including stemness expand beyond mutations, relying on the genetic architecture captured in the chromatin of each cell 9–11. As LSCs share many functional and molecular properties with normal hematopoietic stem cells (HSC), we identified genetic determinants of primitive populations enriched for LSCs and HSCs in comparison with their downstream mature progeny by investigating their chromatin accessibility. Our work reveals how distinct transposable element (TE) subfamilies are used in primitive versus mature populations, functioning as docking sites for stem cell-associated regulators of genome topology, including CTCF, or lineage-specific transcription regulators in primitive and mature populations, respectively. We further show how TE subfamilies accessible in LSCs define docking sites for several oncogenic drivers in AML, namely FLI1, LYL1 and MEIS1. Using chromatin accessibility profiles from a cohort of AML patients, we further show the clinical utility of our TE accessibility-based LSCTE121 scoring scheme to identify patients with high rates of relapse. Collectively, our work reveals how different accessible TE subfamilies serve as genetic determinants of stemness properties in normal and leukemic hematopoietic stem cells.

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