scholarly journals Stem Cells in the Myelodysplastic Syndromes

2021 ◽  
Vol 2 ◽  
Author(s):  
Di Zhan ◽  
Christopher Y. Park
Keyword(s):  
Stem Cells ◽  
Myelodysplastic Syndromes ◽  
Molecular Mechanisms ◽  
Clonal Evolution ◽  
Surface Proteins ◽  
Epigenetic Alterations ◽  
Hematopoietic Stem ◽  
Innate Immune Signaling ◽  
Novel Therapeutic Strategies

The myelodysplastic syndromes (MDS) represent a group of clonal disorders characterized by ineffective hematopoiesis, resulting in peripheral cytopenias and frequent transformation to acute myeloid leukemia (AML). We and others have demonstrated that MDS arises in, and is propagated by malignant stem cells (MDS-SCs), that arise due to the sequential acquisition of genetic and epigenetic alterations in normal hematopoietic stem cells (HSCs). This review focuses on recent advancements in the cellular and molecular characterization of MDS-SCs, as well as their role in mediating MDS clinical outcomes. In addition to discussing the cell surface proteins aberrantly upregulated on MDS-SCs that have allowed the identification and prospective isolation of MDS-SCs, we will discuss the recurrent cytogenetic abnormalities and genetic mutations present in MDS-SCs and their roles in initiating disease, including recent studies demonstrating patterns of clonal evolution and disease progression from pre-malignant HSCs to MDS-SCs. We also will discuss the pathways that have been described as drivers or promoters of disease, including hyperactivated innate immune signaling, and how the identification of these alterations in MDS-SC have led to investigations of novel therapeutic strategies to treat MDS. It is important to note that despite our increasing understanding of the pathogenesis of MDS, the molecular mechanisms that drive responses to therapy remain poorly understood, especially the mechanisms that underlie and distinguish hematologic improvement from reductions in blast burden. Ultimately, such distinctions will be required in order to determine the shared and/or unique molecular mechanisms that drive ineffective hematopoiesis, MDS-SC maintenance, and leukemic transformation.

scholarly journals Reprogramming identifies functionally distinct stages of clonal evolution in myelodysplastic syndromes

Blood ◽  
2019 ◽  
Vol 134 (2) ◽  
pp. 186-198 ◽  
Author(s):  
Jasper Hsu ◽  
Andreea Reilly ◽  
Brian J. Hayes ◽  
Courtnee A. Clough ◽  
Eric Q. Konnick ◽  
...  
Keyword(s):  
Stem Cells ◽  
Induced Pluripotent Stem Cells ◽  
Mitochondrial Function ◽  
Myelodysplastic Syndromes ◽  
Pluripotent Stem Cells ◽  
Somatic Mutations ◽  
Clonal Evolution ◽  
Differentiation Potential ◽  
Hematopoietic Stem ◽  
Induced Pluripotent

Abstract Myeloid neoplasms, including myelodysplastic syndromes (MDS), are genetically heterogeneous disorders driven by clonal acquisition of somatic mutations in hematopoietic stem and progenitor cells (HPCs). The order of premalignant mutations and their impact on HPC self-renewal and differentiation remain poorly understood. We show that episomal reprogramming of MDS patient samples generates induced pluripotent stem cells from single premalignant cells with a partial complement of mutations, directly informing the temporal order of mutations in the individual patient. Reprogramming preferentially captured early subclones with fewer mutations, which were rare among single patient cells. To evaluate the functional impact of clonal evolution in individual patients, we differentiated isogenic MDS induced pluripotent stem cells harboring up to 4 successive clonal abnormalities recapitulating a progressive decrease in hematopoietic differentiation potential. SF3B1, in concert with epigenetic mutations, perturbed mitochondrial function leading to accumulation of damaged mitochondria during disease progression, resulting in apoptosis and ineffective erythropoiesis. Reprogramming also informed the order of premalignant mutations in patients with complex karyotype and identified 5q deletion as an early cytogenetic anomaly. The loss of chromosome 5q cooperated with TP53 mutations to perturb genome stability, promoting acquisition of structural and karyotypic abnormalities. Reprogramming thus enables molecular and functional interrogation of preleukemic clonal evolution, identifying mitochondrial function and chromosome stability as key pathways affected by acquisition of somatic mutations in MDS.

scholarly journals Stem Cells in Myelodysplastic Syndromes and Acute Myeloid Leukemia: First Cousins or Unrelated Entities?

2021 ◽  
Vol 11 ◽  
Author(s):  
Romane Joudinaud ◽  
Thomas Boyer
Keyword(s):  
Stem Cells ◽  
Acute Myeloid Leukemia ◽  
Myelodysplastic Syndromes ◽  
Myeloid Leukemia ◽  
Ribosomal Proteins ◽  
Clonal Evolution ◽  
Significant Risk ◽  
Hematopoietic Stem ◽  
Genetic Characteristics ◽  
Acute Myeloid

Myelodysplastic syndromes (MDSs) are associated with a significant risk of transformation to acute myeloid leukemia (AML), supported by alterations affecting malignant stem cells. This review focuses on the metabolic, phenotypic and genetic characteristics underlying this dynamic evolution, from myelodysplastic stem cells (MDS-SCs) to leukemic stem cells (LSCs). MDS-SCs are more likely to be derived from healthy hematopoietic stem cells (HSCs), whereas LSCs may originate from healthy progenitors, mostly LMPP (lymphoid-primed multipotential progenitors). Moreover, overexpression of CD123 and CLL1 markers by LSCs and MDS-SCs in high risk-MDS [HR-MDS] has led to exciting therapeutic applications. Single-cell sequencing has suggested that clonal evolution in the stem cell compartment was non-linear during MDS initiation and progression to AML, with pre-MDS-SC acquiring distinct additional mutations in parallel, that drive either MDS blast production or AML transformation. In AML and HR-MDS, common metabolic alterations have been identified in malignant stem cells, including activation of the protein machinery and dependence on oxidative phosphorylation. Targeting these metabolic abnormalities could prevent HR-MDS from progressing to AML. Strikingly, in low risk-MDS-SC, the expression of ribosomal proteins is decreased, which may be accompanied by a reduction in protein synthesis.

scholarly journals Myelodysplastic Syndromes in the Postgenomic Era and Future Perspectives for Precision Medicine

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3296
Author(s):  
Ioannis Chanias ◽  
Kristina Stojkov ◽  
Gregor Stehle ◽  
Michael Daskalakis ◽  
Helena Simeunovic ◽  
...  
Keyword(s):  
Precision Medicine ◽  
Myelodysplastic Syndromes ◽  
Clonal Evolution ◽  
Driver Mutations ◽  
Future Perspectives ◽  
Hematopoietic Stem ◽  
Secondary Acute Myeloid Leukemia ◽  
Stem And Progenitor Cells ◽  
Unfit Patients ◽  
Generation Sequencing

Myelodysplastic syndromes (MDS) represent a heterogeneous group of clonal disorders caused by sequential accumulation of somatic driver mutations in hematopoietic stem and progenitor cells (HSPCs). MDS is characterized by ineffective hematopoiesis with cytopenia, dysplasia, inflammation, and a variable risk of transformation into secondary acute myeloid leukemia. The advent of next-generation sequencing has revolutionized our understanding of the genetic basis of the disease. Nevertheless, the biology of clonal evolution remains poorly understood, and the stochastic genetic drift with sequential accumulation of genetic hits in HSPCs is individual, highly dynamic and hardly predictable. These continuously moving genetic targets pose substantial challenges for the implementation of precision medicine, which aims to maximize efficacy with minimal toxicity of treatments. In the current postgenomic era, allogeneic hematopoietic stem cell transplantation remains the only curative option for younger and fit MDS patients. For all unfit patients, regeneration of HSPCs stays out of reach and all available therapies remain palliative, which will eventually lead to refractoriness and progression. In this review, we summarize the recent advances in our understanding of MDS pathophysiology and its impact on diagnosis, risk-assessment and disease monitoring. Moreover, we present ongoing clinical trials with targeting compounds and highlight future perspectives for precision medicine.

scholarly journals First blood: the endothelial origins of hematopoietic progenitors

Angiogenesis ◽  
2021 ◽  
Author(s):  
Giovanni Canu ◽  
Christiana Ruhrberg
Keyword(s):  
Stem Cells ◽  
Molecular Mechanisms ◽  
Vascular Endothelial Cells ◽  
Fetal Liver ◽  
Cell Types ◽  
Yolk Sac ◽  
Vascular Endothelial ◽  
Hematopoietic Stem ◽  
Close Proximity ◽  
Clinical Interest

AbstractHematopoiesis in vertebrate embryos occurs in temporally and spatially overlapping waves in close proximity to blood vascular endothelial cells. Initially, yolk sac hematopoiesis produces primitive erythrocytes, megakaryocytes, and macrophages. Thereafter, sequential waves of definitive hematopoiesis arise from yolk sac and intraembryonic hemogenic endothelia through an endothelial-to-hematopoietic transition (EHT). During EHT, the endothelial and hematopoietic transcriptional programs are tightly co-regulated to orchestrate a shift in cell identity. In the yolk sac, EHT generates erythro-myeloid progenitors, which upon migration to the liver differentiate into fetal blood cells, including erythrocytes and tissue-resident macrophages. In the dorsal aorta, EHT produces hematopoietic stem cells, which engraft the fetal liver and then the bone marrow to sustain adult hematopoiesis. Recent studies have defined the relationship between the developing vascular and hematopoietic systems in animal models, including molecular mechanisms that drive the hemato-endothelial transcription program for EHT. Moreover, human pluripotent stem cells have enabled modeling of fetal human hematopoiesis and have begun to generate cell types of clinical interest for regenerative medicine.

scholarly journals Characterization of Mitochondrial and Extra-mitochondrial Oxygen Consuming Reactions in Human Hematopoietic Stem Cells

2005 ◽  
Vol 280 (28) ◽  
pp. 26467-26476 ◽  
Author(s):  
Claudia Piccoli ◽  
Roberto Ria ◽  
Rosella Scrima ◽  
Olga Cela ◽  
Annamaria D'Aprile ◽  
...  
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Hematopoietic Stem

scholarly journals Identification of leukemic and pre-leukemic stem cells by clonal tracking from single-cell transcriptomics

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Lars Velten ◽  
Benjamin A. Story ◽  
Pablo Hernández-Malmierca ◽  
Simon Raffel ◽  
Daniel R. Leonce ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Single Cell ◽  
Lineage Tracing ◽  
Specific Gene ◽  
Leukemic Stem Cells ◽  
Hematopoietic Stem ◽  
Mutational Status

AbstractCancer stem cells drive disease progression and relapse in many types of cancer. Despite this, a thorough characterization of these cells remains elusive and with it the ability to eradicate cancer at its source. In acute myeloid leukemia (AML), leukemic stem cells (LSCs) underlie mortality but are difficult to isolate due to their low abundance and high similarity to healthy hematopoietic stem cells (HSCs). Here, we demonstrate that LSCs, HSCs, and pre-leukemic stem cells can be identified and molecularly profiled by combining single-cell transcriptomics with lineage tracing using both nuclear and mitochondrial somatic variants. While mutational status discriminates between healthy and cancerous cells, gene expression distinguishes stem cells and progenitor cell populations. Our approach enables the identification of LSC-specific gene expression programs and the characterization of differentiation blocks induced by leukemic mutations. Taken together, we demonstrate the power of single-cell multi-omic approaches in characterizing cancer stem cells.

scholarly journals Pathophysiology of Myelodysplastic Syndromes

Hemato ◽  
2021 ◽  
Vol 2 (3) ◽  
pp. 477-495
Author(s):  
Michaela Fontenay ◽  
Batoul Farhat ◽  
Ismael Boussaid
Keyword(s):  
Myelodysplastic Syndromes ◽  
Tumor Response ◽  
Clonal Evolution ◽  
Epistatic Interactions ◽  
Hematopoietic Stem ◽  
Effector Cells ◽  
Inflammatory State ◽  
Immune Contexture ◽  
Immunosuppressive Cells ◽  
Genetic Events

Ineffective hematopoiesis is the major characteristic of early myelodysplastic syndromes. Its pathophysiology relies on a diversity of mechanisms supported by genetic events that develop in aging hematopoietic stem cells. Deletion and mutations trigger epigenetic modifications, and co-transcriptional and post-transcriptional deregulations of gene expression. Epistatic interactions between mutants may aggravate the phenotype. Amplification of minor subclones containing mutations that promote their growth and suppress the others drives the clonal evolution. Aging also participates in reprogramming the immune microenvironment towards an inflammatory state, which precedes the expansion of immunosuppressive cells such as Tregs and myeloid-derived suppressive cells that alters the anti-tumor response of effector cells. Integrating biomarkers of transcription/translation deregulation and immune contexture will help the design of personalized treatments.

scholarly journals Epigenetic Regulation of Apoptosis and Cell Cycle in Osteosarcoma

Sarcoma ◽  
2011 ◽  
Vol 2011 ◽  
pp. 1-5 ◽  
Author(s):  
Krithi Rao-Bindal ◽  
Eugenie S. Kleinerman
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Regulation ◽  
Molecular Mechanisms ◽  
Genetic Mutations ◽  
Epigenetic Mechanisms ◽  
Epigenetic Alterations ◽  
Novel Therapeutic Strategies ◽  
Cycle Regulation ◽  
Insight Into

The role of genetic mutations in the development of osteosarcoma, such as alterations in p53 and Rb, is well understood. However, the significance of epigenetic mechanisms in the progression of osteosarcoma remains unclear and is increasingly being investigated. Recent evidence suggests that epigenetic alterations such as methylation and histone modifications of genes involved in cell cycle regulation and apoptosis may contribute to the pathogenesis of this tumor. Importantly, understanding the molecular mechanisms of regulation of these pathways may give insight into novel therapeutic strategies for patients with osteosarcoma. This paper serves to summarize the described epigenetic mechanisms in the tumorigenesis of osteosarcoma, specifically those pertaining to apoptosis and cell cycle regulation.

Functional isolation and characterization of human hematopoietic stem cells

Science ◽  
1995 ◽  
Vol 267 (5194) ◽  
pp. 104-108 ◽  
Author(s):  
A. Berardi ◽  
A Wang ◽  
J. Levine ◽  
P Lopez ◽  
D. Scadden
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Hematopoietic Stem ◽  
Isolation And Characterization
Sign in / Sign up

Export Citation Format

Share Document