Clonal hematopoiesis and its role in the development of hematological diseases

Introduction. The formation of blood cells in a healthy individual is ensured by polyclonal hematopoiesis. Recent studies have shown that with age, large clones with a common genetic marker are found in the peripheral blood, i. e. cells originating from a single progenitor cell. This phenomenon is called clonal hematopoiesis. In some cases, people with clonal hematopoiesis develop hematological diseases.Aim — to describe and summarize current data on the relationship between clonal hematopoiesis and hematological diseases.Main findings. This review describes the history of detection of clonal hematopoiesis, its main properties, the most frequent mutations in hematopoietic clones associated with the risk of transformation into myelodysplastic syndrome, and acute myeloid leukemia. The meaning and possible pathogenesis of tumor transformation are discussed.

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N6-Methyladenosine and Rheumatoid Arthritis: A Comprehensive Review

Frontiers in Immunology ◽

10.3389/fimmu.2021.731842 ◽

2021 ◽

Vol 12 ◽

Author(s):

Sha Wu ◽

Xiao-Feng Li ◽

Yuan-Yuan Wu ◽

Su-Qin Yin ◽

Cheng Huang ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Immune Cells ◽

Myeloid Leukemia ◽

Immune Cell ◽

Bone Destruction ◽

Synovial Cell ◽

Biological Processes ◽

Cell Life ◽

History Of ◽

The Relationship

Rheumatoid arthritis (RA), one of the most common autoimmune diseases, is characterized by immune cell infiltration, fibroblast-like synovial cell hyperproliferation, and cartilage and bone destruction. To date, numerous studies have demonstrated that immune cells are one of the key targets for the treatment of RA. N6-methyladenosine (m6A) is the most common internal modification to eukaryotic mRNA, which is involved in the splicing, stability, export, and degradation of RNA metabolism. m6A methylated-related genes are divided into writers, erasers, and readers, and they are critical for the regulation of cell life. They play a significant role in various biological processes, such as virus replication and cell differentiation by controlling gene expression. Furthermore, a growing number of studies have indicated that m6A is associated with the occurrence of numerous diseases, such as lung cancer, bladder cancer, gastric cancer, acute myeloid leukemia, and hepatocellular carcinoma. In this review, we summarize the history of m6A research and recent progress on RA research concerning m6A enzymes. The relationship between m6A enzymes, immune cells, and RA suggests that m6A modification offers evidence for the pathogenesis of RA, which will help in the development of new therapies for RA.

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Bone Marrow Clonogenic Myeloid Progenitors from NPM1-Mutated AML Patients Do Not Harbor the NPM1 Mutation: Implication for the Cell-Of-Origin of NPM1+ AML

Genes ◽

10.3390/genes11010073 ◽

2020 ◽

Vol 11 (1) ◽

pp. 73

Author(s):

Rafael Diaz de la Guardia ◽

Laura González-Silva ◽

Belén López-Millán ◽

Juan José Rodríguez-Sevilla ◽

Matteo L. Baroni ◽

...

Keyword(s):

Bone Marrow ◽

Myeloid Leukemia ◽

Progenitor Cell ◽

Cell Of Origin ◽

Therapeutic Targeting ◽

Npm1 Mutation ◽

Clonal Hematopoiesis ◽

Colony Forming Units ◽

Myeloid Progenitors

The cell-of-origin of NPM1- and FLT3-mutated acute myeloid leukemia (AML) is still a matter of debate. Here, we combined in vitro clonogenic assays with targeted sequencing to gain further insights into the cell-of-origin of NPM1 and FLT3-ITD-mutated AML in diagnostic bone marrow (BM) from nine NPM1+/FLT3-ITD (+/−) AMLs. We reasoned that individually plucked colony forming units (CFUs) are clonal and reflect the progeny of a single stem/progenitor cell. NPM1 and FLT3-ITD mutations seen in the diagnostic blasts were found in only 2/95 and 1/57 individually plucked CFUs, suggesting that BM clonogenic myeloid progenitors in NPM1-mutated and NPM1/FLT3-ITD-mutated AML patients do not harbor such molecular lesions. This supports previous studies on NPM1 mutations as secondary mutations in AML, likely acquired in an expanded pool of committed myeloid progenitors, perhaps CD34−, in line with the CD34−/low phenotype of NPM1-mutated AMLs. This study has important implications on the cell-of-origin of NPM1+ AML, and reinforces that therapeutic targeting of either NPM1 or FLT3-ITD mutations might only have a transient clinical benefit in debulking the leukemia, but is unlikely to be curative since will not target the AML-initiating/preleukemic cells. The absence of NPM1 and FLT3-ITD mutations in normal clonogenic myeloid progenitors is in line with their absence in clonal hematopoiesis of indeterminate potential.

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Epidemiologic features of 65 Creutzfeldt–Jakob disease patients with a history of cadaveric dura mater transplantation in Japan

Epidemiology and Infection ◽

10.1017/s0950268899004240 ◽

2000 ◽

Vol 125 (1) ◽

pp. 201-205 ◽

Cited By ~ 3

Author(s):

Y. NAKAMURA ◽

H. YANAGAWA ◽

T. KITAMOTO ◽

T. SATO

Keyword(s):

Standard Deviation ◽

Latent Period ◽

Dura Mater ◽

Age At Onset ◽

Current Data ◽

History Of ◽

Jakob Disease ◽

Near Future ◽

The Relationship ◽

Epidemiologic Features

A total of 65 cases of Creutzfeldt–Jakob disease with a history of cadaveric dura transplantation in Japan were analysed to clarify the epidemiologic features of such patients and to explore whether other such patients will appear in the future. The age at transplantation averaged 44·4 years with a standard deviation of 14·4 years. The age at onset had an average of 53·0 years with a standard deviation of 14·1 years. The shortest latent period was 14 months, and the longest was 218 months with an average of 103·1 months and a standard deviation of 49·9 months. From the relationship between the calendar year at transplantation and the latent period, other such patients will appear in the near future. The current data suggested that several patients with Creutzfeldt–Jakob disease will occur from those receiving cadaveric dura mater grafts in the near future.

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Personalized Single-Cell Proteogenomics to Distinguish Acute Myeloid Leukemia from Non-Malignant Clonal Hematopoiesis

10.1101/2020.10.22.20216028 ◽

2020 ◽

Author(s):

Laura W. Dillon ◽

Jack Ghannam ◽

Chidera Nosiri ◽

Gege Gui ◽

Meghali Goswami ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Single Cell ◽

Myeloid Leukemia ◽

Residual Disease ◽

Disease Monitoring ◽

Clonal Hematopoiesis ◽

Age Related ◽

The Relationship ◽

Informed Patient ◽

Acute Myeloid

AbstractGenetic mutations associated with acute myeloid leukemia can also be detected in age-related clonal hematopoiesis, making confident assignment of detected variants to malignancy challenging particularly in the post-treatment setting. This has implications for measurable residual disease monitoring, where the relationship between sequencing and flow cytometry is also imperfect. We show, using whole-genome-sequencing informed patient-personalized single-cell DNA and antibody-oligonucleotide sequencing, that it is possible to resolve immunophenotypic identity of clonal architecture.

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Somatic Mutations Predict Acute Myeloid Leukemia Years Before Diagnosis

10.1101/237941 ◽

2017 ◽

Author(s):

Pinkal Desai ◽

Nuria Mencia-Trinchant ◽

Oleksandr Savenkov ◽

Michael S. Simon ◽

Gloria Cheang ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Peripheral Blood ◽

Myeloid Leukemia ◽

Somatic Mutations ◽

Clonal Hematopoiesis ◽

High Risk Populations ◽

The Relationship ◽

Control Study ◽

Acute Myeloid

ABSTRACTBackgroundSomatic mutations observed in clonal hematopoiesis are associated with increased age and risk of hematological malignancies. However, the limited number of acute myeloid leukemia (AML) patients in studies of clonal hematopoiesis thus far has precluded determination of the spectrum of mutations leading to AML and their impact on risk and time to diagnosis.MethodsThe relationship between baseline mutations and subsequent AML was determined in a case-control study design. 212 women eventually diagnosed with AML (median time: 9.8 years) were identified from the Women’s Health Initiative cohort alongside 212 matched AML-free controls. Deep sequencing of 67 genes was performed on DNA isolated from peripheral blood to detect subclonal mutations.ResultsThe presence of any mutation was associated with increased odds of eventual AML (odds ratio [OR] 4.0; 95% confidence interval [CI], 2.5-6.3). These odds were further elevated with mutations in IDH1/2 (OR 8.4; 95% CI, 1.4-51.9), TP53 (OR 54.2; 95% CI, 2.9-1017.7), or spliceosome genes (OR 5.6; 95% CI, 1.5-20.6). Eventual AML diagnosis occurred in all or most participants with mutations in TP53 (N=23/23) or IDH1/2 (N=15/16). Mutations indicated sooner AML diagnosis (median 8.0 vs. 11.9 years; P < 0.001) with TP53 mutations demonstrating increased odds of AML within 5 years (OR 3.6; 95% CI, 1.4-9.1).ConclusionsMutations are present in peripheral blood of AML patients a decade prior to AML diagnosis with mutations in TP53 producing especially rapid presentation. Strategies for monitoring of high-risk populations are needed and clinical trials of potential early interventions can be considered.

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Granulocytic Expression of CD11b/CD18 and Thrombotic Risk in Patients with Myeloproliferative Neoplasms

Journal of Biomedical and Clinical Research ◽

10.2478/jbcr-2021-0005 ◽

2021 ◽

Vol 14 (1) ◽

pp. 47-52

Author(s):

Doroteya K. Todorieva-Todorova ◽

Katya S. Kovacheva ◽

Nikolay T. Tzvetkov ◽

Svetla O. Blazheva ◽

Tzvetan H. Lukanov

Keyword(s):

Blood Cells ◽

Myeloid Leukemia ◽

Clinical Course ◽

Myeloproliferative Neoplasms ◽

Control Group ◽

Thrombotic Complication ◽

Myeloproliferative Disease ◽

Thrombotic Risk ◽

History Of

Summary Myeloproliferative neoplasms (MPN) are clonal hematological conditions characterized by excessive production of one or more cell lines in the bone marrow. The blood cells produced are often hyperactive in their functions, which could lead to complications in the disorder‘s clinical course. We aimed to define the role of granulocytic CD11b/CD18 expression for the thrombotic risk in MPN patients. We investigated 110 patients with a histologically confirmed diagnosis of a myeloproliferative disease and a control group of 46 healthy volunteers. In the patient group, we found an average expression 4.59 times higher than in the control group. The highest expression was found in a subgroup of patients with polycythemia vera – 71.55% of the patients’ neutrophils. In each subgroup with essential thrombocythemia, myelofibrosis, and chronic myeloid leukemia, the patients with a history of thrombotic complication had a higher expression than the patients without such complications.

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Functional and epigenetic phenotypes of humans and mice with DNMT3A Overgrowth Syndrome

Nature Communications ◽

10.1038/s41467-021-24800-7 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Amanda M. Smith ◽

Taylor A. LaValle ◽

Marwan Shinawi ◽

Sai M. Ramakrishnan ◽

Haley J. Abel ◽

...

Keyword(s):

Blood Cells ◽

Myeloid Leukemia ◽

Somatic Mutations ◽

Bisulfite Sequencing ◽

Learning Difficulties ◽

Dominant Negative ◽

Hematopoietic Malignancies ◽

Clonal Hematopoiesis ◽

Pathogenic Variants ◽

Genome Bisulfite Sequencing

AbstractGermline pathogenic variants in DNMT3A were recently described in patients with overgrowth, obesity, behavioral, and learning difficulties (DNMT3AOvergrowth Syndrome/DOS). Somatic mutations in the DNMT3A gene are also the most common cause of clonal hematopoiesis, and can initiate acute myeloid leukemia (AML). Using whole genome bisulfite sequencing, we studied DNA methylation in peripheral blood cells of 11 DOS patients and found a focal, canonical hypomethylation phenotype, which is most severe with the dominant negative DNMT3AR882H mutation. A germline mouse model expressing the homologous Dnmt3aR878H mutation phenocopies most aspects of the human DOS syndrome, including the methylation phenotype and an increased incidence of spontaneous hematopoietic malignancies, suggesting that all aspects of this syndrome are caused by this mutation.

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The evolution of hematopoietic cells under cancer therapy

Nature Communications ◽

10.1038/s41467-021-24858-3 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Oriol Pich ◽

Albert Cortes-Bullich ◽

Ferran Muiños ◽

Marta Pratcorona ◽

Abel Gonzalez-Perez ◽

...

Keyword(s):

Blood Cells ◽

Myeloid Leukemia ◽

Hematopoietic Cells ◽

Clonal Expansion ◽

Selective Pressures ◽

Clonal Hematopoiesis ◽

Mutational Signature ◽

Mutation Burden ◽

Cytotoxic Treatment ◽

Somatic Tissues

AbstractChemotherapies may increase mutagenesis of healthy cells and change the selective pressures in tissues, thus influencing their evolution. However, their contributions to the mutation burden and clonal expansions of healthy somatic tissues are not clear. Here, exploiting the mutational footprint of some chemotherapies, we explore their influence on the evolution of hematopoietic cells. Cells of Acute Myeloid Leukemia (AML) secondary to treatment with platinum-based drugs show the mutational footprint of these drugs, indicating that non-malignant blood cells receive chemotherapy mutations. No trace of the 5-fluorouracil (5FU) mutational signature is found in AMLs secondary to exposure to 5FU, suggesting that cells establishing the leukemia could be quiescent during treatment. Using the platinum-based mutational signature as a barcode, we determine that the clonal expansion originating the secondary AMLs begins after the start of the cytotoxic treatment. Its absence in clonal hematopoiesis cases is consistent with the start of the clonal expansion predating the exposure to platinum-based drugs.

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The relationship of the scleractinian corals to the rugose corals

Paleobiology ◽

10.1017/s0094837300025707 ◽

1980 ◽

Vol 6 (02) ◽

pp. 146-160 ◽

Cited By ~ 29

Author(s):

William A. Oliver

Keyword(s):

Critical Points ◽

Scleractinian Corals ◽

Convincing Evidence ◽

Early Triassic ◽

Rugose Corals ◽

History Of ◽

The Subject ◽

Relationship Of ◽

The Relationship ◽

Biologic Factors

The Mesozoic-Cenozoic coral Order Scleractinia has been suggested to have originated or evolved (1) by direct descent from the Paleozoic Order Rugosa or (2) by the development of a skeleton in members of one of the anemone groups that probably have existed throughout Phanerozoic time. In spite of much work on the subject, advocates of the direct descent hypothesis have failed to find convincing evidence of this relationship. Critical points are:(1) Rugosan septal insertion is serial; Scleractinian insertion is cyclic; no intermediate stages have been demonstrated. Apparent intermediates are Scleractinia having bilateral cyclic insertion or teratological Rugosa.(2) There is convincing evidence that the skeletons of many Rugosa were calcitic and none are known to be or to have been aragonitic. In contrast, the skeletons of all living Scleractinia are aragonitic and there is evidence that fossil Scleractinia were aragonitic also. The mineralogic difference is almost certainly due to intrinsic biologic factors.(3) No early Triassic corals of either group are known. This fact is not compelling (by itself) but is important in connection with points 1 and 2, because, given direct descent, both changes took place during this only stage in the history of the two groups in which there are no known corals.

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Investigating the Relationship Between Self-Esteem and Stigma Among Young Adults With History of Suicide Attempts

Crisis ◽

10.1027/0227-5910/a000399 ◽

2016 ◽

Vol 37 (4) ◽

pp. 265-270 ◽

Cited By ~ 10

Author(s):

Meshan Lehmann ◽

Matthew R. Hilimire ◽

Lawrence H. Yang ◽

Bruce G. Link ◽

Jordan E. DeVylder

Keyword(s):

Young Adults ◽

Suicide Attempts ◽

Self Esteem ◽

High Risk Population ◽

High Functioning ◽

People With Mental Illness ◽

History Of ◽

The Individual ◽

The Impact ◽

The Relationship

Abstract. Background: Self-esteem is a major contributor to risk for repeated suicide attempts. Prior research has shown that awareness of stigma is associated with reduced self-esteem among people with mental illness. No prior studies have examined the association between self-esteem and stereotype awareness among individuals with past suicide attempts. Aims: To understand the relationship between stereotype awareness and self-esteem among young adults who have and have not attempted suicide. Method: Computerized surveys were administered to college students (N = 637). Linear regression analyses were used to test associations between self-esteem and stereotype awareness, attempt history, and their interaction. Results: There was a significant stereotype awareness by attempt interaction (β = –.74, p = .006) in the regression analysis. The interaction was explained by a stronger negative association between stereotype awareness and self-esteem among individuals with past suicide attempts (β = –.50, p = .013) compared with those without attempts (β = –.09, p = .037). Conclusion: Stigma is associated with lower self-esteem within this high-functioning sample of young adults with histories of suicide attempts. Alleviating the impact of stigma at the individual (clinical) or community (public health) levels may improve self-esteem among this high-risk population, which could potentially influence subsequent suicide risk.

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