scholarly journals Clonal Hematopoiesis, Cardiovascular Diseases and Hematopoietic Stem Cells

2020 ◽  
Vol 21 (21) ◽  
pp. 7902
Author(s):  
Oleg Kandarakov ◽  
Alexander Belyavsky
Keyword(s):  
Cardiovascular Diseases ◽  
Cell Biology ◽  
Driving Force ◽  
The Elderly ◽  
Stem Cell Biology ◽  
Driver Genes ◽  
Hematopoietic Stem ◽  
Clonal Hematopoiesis ◽  
Somatic Mutagenesis ◽  
Progression Of Atherosclerosis

Cardiovascular diseases and cancer, the leading causes of morbidity and mortality in the elderly, share some common mechanisms, in particular inflammation, contributing to their progression and pathogenesis. However, somatic mutagenesis, a driving force in cancer development, has not been generally considered as an important factor in cardiovascular disease pathology. Recent studies demonstrated that during normal aging, somatic mutagenesis occurs in blood cells, often resulting in expansion of mutant clones that dominate hematopoiesis at advanced age. This clonal hematopoiesis is primarily associated with mutations in certain leukemia-related driver genes and, being by itself relatively benign, not only increases the risks of subsequent malignant hematopoietic transformation, but, unexpectedly, has a significant impact on progression of atherosclerosis and cardiovascular diseases. In this review, we discuss the phenomenon of clonal hematopoiesis, the most important genes involved in it, its impact on cardiovascular diseases, and relevant aspects of hematopoietic stem cell biology.

scholarly journals 2002 – GENETIC PREDISPOSITION TO MYELOPROLIFERATIVE NEOPLASMS IMPLICATES HEMATOPOIETIC STEM CELL BIOLOGY

2020 ◽  
Vol 88 ◽  
pp. S27
Author(s):  
Satish Nandakumar ◽  
Erik Bao ◽  
Xiaotian Liao ◽  
Alexander Bick ◽  
Juha Karjalainen ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Genetic Predisposition ◽  
Cell Biology ◽  
Myeloproliferative Neoplasms ◽  
Stem Cell Biology ◽  
Hematopoietic Stem

scholarly journals Discovering the drivers of clonal hematopoiesis

2020 ◽  
Author(s):  
Oriol Pich ◽  
Iker Reyes-Salazar ◽  
Abel Gonzalez-Perez ◽  
Nuria Lopez-Bigas
Keyword(s):  
Positive Selection ◽  
Molecular Mechanisms ◽  
Somatic Mutations ◽  
Cancer Genomics ◽  
Variant Calling ◽  
Selective Advantage ◽  
Cancer Genes ◽  
Driver Genes ◽  
Hematopoietic Stem ◽  
Clonal Hematopoiesis

AbstractMutations in genes that confer a selective advantage to hematopoietic stem cells (HSCs) in certain conditions drive clonal hematopoiesis (CH). While some CH drivers have been identified experimentally or through epidemiological studies, the compendium of all genes able to drive CH upon mutations in HSCs is far from complete. We propose that identifying signals of positive selection in blood somatic mutations may be an effective way to identify CH driver genes, similarly as done to identify cancer genes. Using a reverse somatic variant calling approach, we repurposed whole-genome and whole-exome blood/tumor paired samples of more than 12,000 donors from two large cancer genomics cohorts to identify blood somatic mutations. The application of IntOGen, a robust driver discovery pipeline, to blood somatic mutations across both cohorts, and more than 24,000 targeted sequenced samples yielded a list of close to 70 genes with signals of positive selection in CH, available at http://www.intogen.org/ch. This approach recovers all known CH genes, and discovers novel candidates. Generating this compendium is an essential step to understand the molecular mechanisms of CH and to accurately detect individuals with CH to ascertain their risk to develop related diseases.

Hematopoietic Stem Cell Biology

Hematology ◽  
2018 ◽  
pp. 95-110.e13
Author(s):  
Marlies P. Rossmann ◽  
Stuart H. Orkin ◽  
John P. Chute
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Cell Biology ◽  
Stem Cell Biology ◽  
Hematopoietic Stem

Recent advances in hematopoietic stem cell biology

2004 ◽  
Vol 11 (6) ◽  
pp. 392-398 ◽  
Author(s):  
Jesper Bonde ◽  
David A Hess ◽  
Jan A Nolta
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Cell Biology ◽  
Stem Cell Biology ◽  
Hematopoietic Stem ◽  
Recent Advances

scholarly journals Common Sources of Inflammation and Their Impact on Hematopoietic Stem Cell Biology

2020 ◽  
Vol 6 (3) ◽  
pp. 96-107 ◽  
Author(s):  
Daniel Hormaechea-Agulla ◽  
Duy T. Le ◽  
Katherine Y. King
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Cell Biology ◽  
Stem Cell Biology ◽  
Hematopoietic Stem

Leukemic CD34+CD38- Cells Display Conserved Differential Expression of Many ATP Binding-Cassette Transporter Genes.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1380-1380
Author(s):  
Marc H.G.P. Raaijmakers ◽  
Elke P.L.M. de Grouw ◽  
Louis T.F. van de Locht ◽  
Bert A. van der Reijden ◽  
Theo J.M. de Witte ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Stem Cell ◽  
Abc Transporters ◽  
Cell Biology ◽  
Cell Fraction ◽  
Atp Binding ◽  
Stem Cell Biology ◽  
Hematopoietic Stem ◽  
Atp Binding Cassette

Abstract In most cases of acute myeloid leukemia (AML) CD34+CD38− cells are considered to be stem cells, responsible for the maintenance and relapse of AML. ATP binding cassette transporters function in the extrusion of xenobiotics and chemotherapeutical compounds, and may be involved in therapy resistance. Elucidation of mechanisms conferring drug resistance to CD34+CD38− cells is essential to provide novel targets for stem cell eradication in AML. We studied gene expression of all 45 transmembrane ABC transporters (the complete ABCA, B, C, D and G family) in human hematopoietic CD34+CD38− cells and more committed CD34+CD38+ progenitor cells, from healthy donors and patients with non-hematological diseases (N=11) and AML patients (N=11). Gene expression was assessed using a novel real-time RT-PCR approach with micro fluidic cards. In normal CD34+CD38− cells 36 ABC transporters were expressed, 22 of these displayed significant higher expression in the CD34+CD38− cell fraction compared to the CD34+CD38+ cell fraction. In addition to the known stem cell transporters (ABCB1, ABCC1 and ABCG2) these differential expressed genes included many members not previously associated with stem cell biology. In AML the ABC transporter expression profile was largely conserved, including expression of all 13 known drug transporters. These data suggest an important role for many ABC transporters in hematopoietic stem cell biology. In addition, the preferential expression of a high number of drug transport related transporters predicts that broad spectrum inhibition of ABC transporters is likely to be required for CD34+38− stem cell eradication in AML. This approach will, apart from affecting the leukemic stem cells, equally affect the normal stem cells.

The Role of Nucleophosmin In Hematopoietic Stem Cells and the Pathogenesis of Myelodysplastic Syndrome

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 95-95 ◽  
Author(s):  
Keisuke Ito ◽  
Paolo Sportoletti ◽  
John G Clohessy ◽  
Grisendi Silvia ◽  
Pier Paolo Pandolfi
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Myelodysplastic Syndrome ◽  
Cell Biology ◽  
De Novo ◽  
Stem Cell Biology ◽  
Hematopoietic Stem

Abstract Abstract 95 Myelodysplastic syndrome (MDS) is an incurable stem cell disorder characterized by ineffective hematopoiesis and an increased risk of leukemia transformation. Nucleophosmin (NPM) is directly implicated in primitive hematopoiesis, the pathogenesis of hematopoietic malignancies and more recently of MDS. However, little is known regarding the molecular role and function of NPM in MDS pathogenesis and in stem cell biology. Here we present data demonstrating that NPM plays a critical role in the maintenance of hematopoietic stem cells (HSCs) and the transformation of MDS into leukemia. NPM is located on chromosome 5q and is frequently lost in therapy-related and de novo MDS. We have previously shown that Npm1 acts as a haploinsufficient tumor suppressor in the hematopoietic compartment and Npm1+/− mice develop a hematologic syndrome with features of human MDS, including increased susceptibility to leukemogenesis. As HSCs have been demonstrated to be the target of the primary neoplastic event in MDS, a functional analysis of the HSC compartment is essential to understand the molecular mechanisms in MDS pathogenesis. However, the role of NPM in adult hematopoiesis remains largely unknown as Npm1-deficiency leads to embryonic lethality. To investigate NPM function in adult hematopoiesis, we have generated conditional knockout mice of Npm1, using the Cre-loxP system. Analysis of Npm1 conditional mutants crossed with Mx1-Cre transgenic mice reveals that Npm1 plays a crucial role in adult hematopoiesis and ablation of Npm1 in adult HSCs leads to aberrant cycling and followed by apoptosis. Analysis of cell cycle status revealed that HSCs are impaired in their ability to maintain quiescence after Npm1-deletion and are rapidly depleted in vivo as well as in vitro. Competitive reconstitution assay revealed that Npm1 acts cell-autonomously to maintain HSCs. Conditional inactivation of Npm1 leads to an MDS phenotype including a profoundly impaired ability to differentiate into cells of the erythroid lineage, megakaryocyte dyspoiesis and centrosome amplification. Furthermore, Npm1 loss evokes a p53-dependent response and Npm1-deleted HSCs undergo apoptosis in vivo and in vitro. Strikingly, transfer of the Npm1 mutation into a p53-null background rescued the apoptosis of Npm1-ablated HSCs and resulted in accelerated transformation to an aggressive and lethal form of acute myeloid leukemia. Our findings highlight the crucial role of NPM in stem cell biology and identify a new mechanism by which MDS can progress to leukemia. This has important therapeutic implications for de novo MDS as well as therapy-related MDS, which is known to rapidly evolve to leukemia with frequent loss or mutation of TRP53. Disclosures: No relevant conflicts of interest to declare.

Sign in / Sign up

Export Citation Format

Share Document