scholarly journals Transcriptional regulation of HSCs in Aging and MDS reveals DDIT3 as a Potential Driver of Transformation

2021 ◽  
Author(s):  
Nerea Berastegui ◽  
Marina Ainciburu ◽  
Juan P. Romero ◽  
Ana Alfonso-Pierola ◽  
Céline Philippe ◽  
...  
Keyword(s):  
Transcriptional Profiling ◽  
Erythroid Differentiation ◽  
Genetic Alterations ◽  
List Type ◽  
Hematopoietic Stem ◽  
Associated Lesions ◽  
Key Points ◽  
Transcriptional Rewiring ◽  
Human Hscs ◽  
Transcriptional State

ABSTRACTMyelodysplastic syndromes (MDS) are clonal hematopoietic stem cell (HSC) malignancies characterized by ineffective hematopoiesis with increased incidence in elderly individuals. Genetic alterations do not fully explain the molecular pathogenesis of the disease, indicating that other types of lesions may play a role in its development. In this work, we analyzed the transcriptional lesions of human HSCs, demonstrating how aging and MDS are characterized by a complex transcriptional rewiring that manifests as diverse linear and non-linear transcriptional dynamisms. While aging-associated lesions seemed to predispose elderly HSCs to myeloid transformation, disease-specific alterations may be involved in triggering MDS development. Among MDS-specific lesions, we detected the overexpression of the transcription factor DDIT3. Exogenous upregulation of DDIT3 in human healthy HSCs induced an MDS-like transcriptional state, and a delay in erythropoiesis, with an accumulation of cells in early stages of erythroid differentiation, as determined by single-cell RNA-sequencing. Increased DDIT3 expression was associated with downregulation of transcription factors required for normal erythropoiesis, such as KLF1, TAL1 or SOX6, and with a failure in the activation of their erythroid transcriptional programs. Finally, DDIT3 knockdown in CD34+ cells from MDS patients was able to restore erythropoiesis, as demonstrated by immunophenotypic and transcriptional profiling. These results demonstrate that DDIT3 may be a driver of MDS transformation, and a potential therapeutic target to restore the inefficient erythropoiesis characterizing these patients.KEY POINTSHuman HSCs undergo a complex transcriptional rewiring in aging and MDS that may contribute to myeloid transformation.DDIT3 overexpression induces a failure in the activation of erythroid transcriptional programs, leading to inefficient erythropoiesis.

scholarly journals IDH1 mutation contributes to myeloid dysplasia in mice by disturbing heme biosynthesis and erythropoiesis

Blood ◽  
2020 ◽  
Author(s):  
Yu Gu ◽  
Risheng Yang ◽  
Ying Yang ◽  
Yuanlin Zhao ◽  
Andrew Wakeham ◽  
...  
Keyword(s):  
Erythroid Differentiation ◽  
Genetic Alterations ◽  
Idh1 Mutation ◽  
Heme Biosynthesis ◽  
Heme Oxygenase 1 ◽  
Erythroid Cells ◽  
Hematopoietic Stem ◽  
Idh Mutations ◽  
Mutant Idh1 ◽  
New Treatments

Isocitrate dehydrogenase (IDH) mutations are common genetic alterations in myeloid disorders, including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Epigenetic changes, including abnormal histone and DNA methylation, have been implicated in the pathogenic build-up of hematopoietic progenitors, but it is still unclear whether and how IDH mutations themselves affect hematopoiesis. Here, we show that IDH1-mutant mice develop myeloid dysplasia in that these animals exhibit anemia, ineffective erythropoiesis, increased immature progenitor and erythroblast. In erythroid cells of these mice, D-2-hydroxyglutarate (D-2HG), an aberrant metabolite produced by the mutant IDH1 enzyme, inhibits oxoglutarate dehydrogenase (OGDH) activity and diminishes succinyl-CoA production. This succinyl-CoA deficiency attenuates heme biosynthesis in IDH1-mutant hematopoietic cells, thus blocking erythroid differentiation at the late erythroblast stage and the erythroid commitment of hematopoietic stem cells (HSC), while the exogenous succinyl-CoA or 5-ALA rescues erythropoiesis in IDH1-mutant erythroid cells. Heme deficiency also impairs heme oxygenase-1 (HO-1) expression, which reduces levels of important heme catabolites such as biliverdin and bilirubin. These deficits result in accumulation of excessive reactive oxygen species (ROS) that induce the cell death of IDH1-mutant erythroid cells. Our results clearly demonstrate the essential role of IDH1 in normal erythropoiesis and show how its mutation leads to myeloid disorders. Our data thus have important implications for the devising of new treatments for IDH-mutant tumors.

scholarly journals Exacerbation of mitochondrial fission in human CD34+ cells halts erythropoiesis and hemoglobin biosynthesis

2020 ◽  
Author(s):  
Alvaro M. Gonzalez-Ibanez ◽  
Lina M. Ruiz ◽  
Erik Jensen ◽  
Cesar A. Echeverria ◽  
Valentina Romero ◽  
...  
Keyword(s):  
Mitochondrial Permeability Transition ◽  
Mitochondrial Dynamics ◽  
Hot Spot ◽  
Erythroid Differentiation ◽  
Metabolic Reprogramming ◽  
Mitochondrial Morphology ◽  
List Type ◽  
Hematopoietic Stem ◽  
Human Cd34 ◽  
Hemoglobin Biosynthesis

AbstractErythropoiesis is the most powerful cellular differentiation and proliferation system, with a production of 1011 cells per day. In this fine-tuned process, the hematopoietic stem cells (HSCs) generate erythroid progenitors, which proliferate and mature into erythrocytes. During erythropoiesis, mitochondria are reprogrammed to drive the differentiation process before finally being eliminated by mitophagy. In erythropoiesis, mitochondrial dynamics (MtDy) is expected to be a regulatory key point that has not been described previously. We described that a specific MtDy pattern is occurring in human erythropoiesis from EPO-induced human CD34+ cells, characterized by a predominant mitochondrial fusion at early stages followed by predominant fission at late stages. The fusion protein MFN1 and the fission protein FIS1 are shown to play a key role in the accurate progression of erythropoiesis. Fragmentation of the mitochondrial web by the overexpression of FIS1 (gain of fission) resulted in both the inhibition of hemoglobin biosynthesis and the arrest of erythroid differentiation, keeping cells in immature differentiation stages. These cells showed specific mitochondrial features as compared with control cells, such as an increase in round and large mitochondria morphology, low mitochondrial membrane potential and a drop in the expression of the respiratory complexes II and IV. Interestingly, treatment with the mitochondrial permeability transition pore (mPTP) inhibitor cyclosporin A, rescued mitochondrial morphology, hemoglobin biosynthesis and erythropoiesis. Studies presented in this work revealed MtDy as a hot spot in the regulation of erythroid differentiation which might be signaling downstream for metabolic reprogramming through the aperture/close of the mPTP.Key Points-. Excessive fission disrupts erythroid progression, heme biosynthesis and mitochondrial function, keeping cells mostly in progenitors and proerythroblast stage.-. Mitochondrial Dynamics signaling for erythroid differentiation involves FIS1 and the mPTP

scholarly journals Aid is a key regulator of myeloid/erythroid differentiation and DNA methylation in hematopoietic stem/progenitor cells

Blood ◽  
2017 ◽  
Vol 129 (13) ◽  
pp. 1779-1790 ◽  
Author(s):  
Hiroyoshi Kunimoto ◽  
Anna Sophia McKenney ◽  
Cem Meydan ◽  
Kaitlyn Shank ◽  
Abbas Nazir ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Progenitor Cells ◽  
Erythroid Differentiation ◽  
Genetic Loci ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Key Points

Key Points Aid loss leads to altered differentiation, transcription, and methylation in specific genetic loci in hematopoietic stem/progenitor cells. Aid loss does not contribute to enhanced HSC self-renewal or cooperate with Flt3-ITD in myeloid leukemogenesis.

scholarly journals Distinct signaling programs control human hematopoietic stem cell survival and proliferation

Blood ◽  
2017 ◽  
Vol 129 (3) ◽  
pp. 307-318 ◽  
Author(s):  
David J. H. F. Knapp ◽  
Colin A. Hammond ◽  
Nima Aghaeepour ◽  
Paul H. Miller ◽  
Davide Pellacani ◽  
...  
Keyword(s):  
Stem Cell ◽  
Growth Factor ◽  
Cell Survival ◽  
Hematopoietic Stem Cell ◽  
Hematopoietic Stem ◽  
Key Points ◽  
Stem Cell Survival ◽  
Human Hscs ◽  
Signaling Activity ◽  
Cell Survival And Proliferation

Key Points Human HSCs show higher tonic signaling activity in multiple pathways than MPPs. Growth factor–activated AKT and β-catenin in human HSCs regulate their survival and mitogenesis.

scholarly journals The dynamic interactive network of long non-coding RNAs and chromatin accessibility facilitates erythroid differentiation

2021 ◽  
Author(s):  
Yunxiao Ren ◽  
Junwei Zhu ◽  
Yuanyuan Han ◽  
Pin Li ◽  
Hongzhu Qu ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Specific Interaction ◽  
Erythroid Differentiation ◽  
Chromatin Accessibility ◽  
List Type ◽  
Erythroid Progenitor ◽  
Hematopoietic Stem ◽  
Interactive Network ◽  
Non Coding Rnas ◽  
Terminal Erythroid Differentiation

AbstractErythroid differentiation is a dynamic process regulated by multiple factors, while the interaction between long non-coding RNAs and chromatin accessibility and its influence on erythroid differentiation remains unclear. To elucidate this interaction, we employed hematopoietic stem cells, multipotent progenitor cells, common myeloid progenitor cells, megakaryocyte-erythroid progenitor cells, and erythroblasts from human cord blood as an erythroid differentiation model to explore the coordinated regulatory functions of lncRNAs and chromatin accessibility in erythropoiesis by integrating RNA-Seq and ATAC-Seq data. We revealed that the integrated network of chromatin accessibility and LncRNAs exhibits stage-specific changes throughout the erythroid differentiation process, and that the changes at the EB stage of maturation are dramatic. We identified a subset of stage-specific lncRNAs and transcription factors (TFs) that coordinate with chromatin accessibility during erythroid differentiation, in which lncRNAs are key regulators of terminal erythroid differentiation via a lncRNA-TF-gene network. LncRNA PCED1B-AS1 was revealed to regulate terminal erythroid differentiation by coordinating GATA1 dynamically binding to the chromatin during erythroid differentiation. DANCR, another lncRNA that is highly expressed at the MEP stage, was verified to promote erythroid differentiation by compromising megakaryocyte differentiation and coordinating with chromatin accessibility and TFs, such as RUNX1. Overall, our results identified the interactive network of lncRNAs and chromatin accessibility in erythropoiesis and provide novel insights into erythroid differentiation and abundant resources for further study.Key PointsLncRNAs regulate erythroid differentiation through coordinating with chromatin accessibility.The integrative multi-omics analysis reveals stage-specific interaction network of LncRNAs and chromatin accessibility in erythropoiesis.

scholarly journals Hepatic Leukemia Factor supports the propagation of leukemia and hematopoietic stem cell function during stress-induced regeneration

2021 ◽  
Author(s):  
Aurélie Baudet ◽  
Karolina Komorowska ◽  
Simon Hultmark ◽  
Marion Chapellier ◽  
Kenichi Miharada ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Function ◽  
Molecular Networks ◽  
List Type ◽  
Hematopoietic Stem ◽  
Disease Propagation ◽  
Hematopoietic Recovery ◽  
Key Points ◽  
Essential Transcription Factor ◽  
Dependent Mechanism

AbstractThe processes regulating hematopoietic stem cells (HSC) during aging are not fully understood1, but it is clear that the incidence of hematological malignancies increases with age, highlighting the importance of unravelling the cellular and molecular networks involved. Recently, we identified Hepatic Leukemia Factor (HLF) as an essential transcription factor in maintaining the HSC pool during regeneration2 and showed that failure to downregulate HLF leads to disrupted differentiation3.Here, we found that HLF is dispensable for hematopoiesis during systemic aging, but needed during stress-induced hematopoietic recovery of aged HSC after transplantation. Additionally, HLF was dispensable for leukemic initiation but required for disease propagation. Taken together, our findings demonstrate the existence of a HLF-dependent mechanism that uncouples stress-induced regeneration from hematopoietic homeostasis during aging, that can be used by malignant cells to gain stem cell properties to propagate the disease.Key pointsHLF is dispensable for HSC function and hematopoietic homeostasis during physiological aging, but crucial during stress induced regeneration.HLF supports the propagation of leukemia-initiating cells

scholarly journals High-level correction of the sickle mutation amplified in vivo during erythroid differentiation

2018 ◽  
Author(s):  
Wendy Magis ◽  
Mark A. DeWitt ◽  
Stacia K. Wyman ◽  
Jonathan T. Vu ◽  
Seok-Jin Heo ◽  
...  
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Genetic Disorders ◽  
Erythroid Differentiation ◽  
Hematopoietic Stem ◽  
Curative Therapy ◽  
Human Hscs ◽  
High Level

ABSTRACTSickle Cell Disease (SCD), one of the world’s most common genetic disorders, causes anemia and progressive multiorgan damage that typically shortens lifespan by decades; currently there is no broadly applicable curative therapy. Here we show that Cas9 RNP-mediated gene editing with an ssDNA oligonucleotide donor yields markerless correction of the sickle mutation in more than 30% of long-term engrafting human hematopoietic stem cells (HSCs), using a selection-free protocol that is directly applicable to a clinical setting. We further find that in vivo erythroid differentiation markedly enriches for corrected ß-globin alleles. Adoption of a high-fidelity Cas9 variant demonstrates that this approach can yield efficient editing with almost no off-target events. These findings indicate that the sickle mutation can be corrected in human HSCs at curative levels with a streamlined protocol that is ready to be translated into a therapy.ONE SENTENCE SUMMARYCas9-mediated correction of the sickle mutation in human hematopoietic stem cells can be accomplished at curative levels.

scholarly journals Pediatric MDS and bone marrow failure-associated germline mutations in SAMD9 and SAMD9L impair multiple pathways in primary hematopoietic cells

Leukemia ◽  
2021 ◽  
Author(s):  
Melvin E. Thomas ◽  
Sherif Abdelhamed ◽  
Ryan Hiltenbrand ◽  
Jason R. Schwartz ◽  
Sadie Miki Sakurada ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Failure ◽  
Transcriptional Profiling ◽  
Hematopoietic Cells ◽  
Protein Translation ◽  
Germline Mutations ◽  
Hematopoietic Stem ◽  
Monosomy 7 ◽  
Cellular Environment ◽  
Primary Mouse

AbstractPediatric myelodysplastic syndromes (MDS) are a heterogeneous disease group associated with impaired hematopoiesis, bone marrow hypocellularity, and frequently have deletions involving chromosome 7 (monosomy 7). We and others recently identified heterozygous germline mutations in SAMD9 and SAMD9L in children with monosomy 7 and MDS. We previously demonstrated an antiproliferative effect of these gene products in non-hematopoietic cells, which was exacerbated by their patient-associated mutations. Here, we used a lentiviral overexpression approach to assess the functional impact and underlying cellular processes of wild-type and mutant SAMD9 or SAMD9L in primary mouse or human hematopoietic stem and progenitor cells (HSPC). Using a combination of protein interactome analyses, transcriptional profiling, and functional validation, we show that SAMD9 and SAMD9L are multifunctional proteins that cause profound alterations in cell cycle, cell proliferation, and protein translation in HSPCs. Importantly, our molecular and functional studies also demonstrated that expression of these genes and their mutations leads to a cellular environment that promotes DNA damage repair defects and ultimately apoptosis in hematopoietic cells. This study provides novel functional insights into SAMD9 and SAMD9L and how their mutations can potentially alter hematopoietic function and lead to bone marrow hypocellularity, a hallmark of pediatric MDS.

scholarly journals PAX5 is a tumor suppressor in mouse mutagenesis models of acute lymphoblastic leukemia

Blood ◽  
2015 ◽  
Vol 125 (23) ◽  
pp. 3609-3617 ◽  
Author(s):  
Jinjun Dang ◽  
Lei Wei ◽  
Jeroen de Ridder ◽  
Xiaoping Su ◽  
Alistair G. Rust ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Tumor Suppressor ◽  
Lymphoblastic Leukemia ◽  
Genetic Alterations ◽  
Genetic Alteration ◽  
Human Leukemia ◽  
Key Points ◽  
Leukemia Development ◽  
Common Target ◽  
Mouse Mutagenesis

Key Points Heterozygous alterations of Pax5, the most common target of genetic alteration in ALL, promote ALL in mouse mutagenesis models. Leukemia development is accompanied by the acquisition of genetic alterations commonly observed in human leukemia.

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