Chronic Myelomonocytic Leukemia, Myelodysplastic Syndromes, Old Age, Severe/Moderate Coronavirus
Conditions
Keywords
Calprotectin, hematopoiesis, COVID-19
Brief summary
The purpose of this study is to provide new insights into the pathophysiology of emergency hematopoiesis detected in severe COVID-19 patients. The investigators aim to explore the ability of calprotectin to induce an immunosuppressive myeloid program at the hematopoietic stem and progenitor cell (HSPC) level, and to identify the receptor(s) involved in this effect. Since patients with a hematological malignancy demonstrate a very high propensity to develop a severe COVID-19, the investigators will explore how HSPCs collected from patients with a myeloid malignancy respond to calprotectin.
Detailed description
Emergency myelopoiesis in response to SARS-CoV-2 infection produce immunosuppressive myeloid cells with accumulation of immature granulocytes and loss of non-classical monocytes. Excessive release of calprotectin, the dimer of S100A8/A9 alarmins, by immature granulocytes and activated monocytes reflects this situation. A role of calprotectin has been previously described in the initiation and progression of chronic hematological malignancies such as myelodysplastic syndromes. To provide a rationale for the targeting of alarmin-driven signaling pathways and limit the pathogenic inflammatory response to SARS-CoV-2 infection, the role of calprotectin in the production of immunosuppressive cells from the bone marrow hematopoietic stem and progenitors cells needs to be investigated in patients with severe COVID-19 in comparison with patients with chronic myeloid malignancies (such as chronic myelomonocytic leukemia and myelodysplastic syndromes) and with age-mached healthy controls. A comprehensive and integrated multiomics approach will be used to decipher the features of immunosuppressive cells and identify therapeutic targets in deregulated pathways.
Interventions
BIOLOGICALBlood samples
blood
Sponsors
Assistance Publique - Hôpitaux de Paris
Gustave Roussy, Cancer Campus, Grand Paris
URC-CIC Paris Descartes Necker Cochin
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
DIAGNOSTIC
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
Criteria for all groups: * Adults ≥ 18 years * Dated and signed inform consent \* * \* : written informed consent of relative (trusted person, close family) in case of emergency procedure, by default emergency inclusion notified in medical file and pursuance consent sought. * Affiliation with a social security scheme Criteria for control group: * Age-matched healthy donors Criteria for chronic myeloid malignancies: * A diagnosis of low or high-risk myelodysplastic syndromes according to the WHO 2016 classification * A diagnosis of dysplastic or proliferative chronic myelomonocytic leukemia according to WHO 2016 Criteria for COVID-19 patients: * Patients with a recent diagnosis (\<7 days since first symptoms) of moderate or severe COVID-19
Exclusion criteria
* Pregnant women * Minor patient or major under protection * Patients with COVID-19 infection and active cancer or a history of cancer within the last 6 months * Patients with COVID-19 and severe comorbidities including cardiovascular or respiratory diseases, unbalanced diabetes, obesity (IMC \>29) * Patient on AME (state medical aid)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Differential gene expression and epigenetic signature of COVID-19 or leukemic versus normal HSC using CITE-seq and ATAC-seq | 12 months | Hematopoietic stem and progenitor cells from patients with severe or moderate COVID-19 or chronic myeloid malignancies or controls will be purified for analyses of transcriptome and chromatin conformation, and also functionally characterized using in vitro culture systems. Results will be compared between the three groups. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Ex vivo testing of calprotectin-receptor interaction inhibitor | During the last 6 months of the study | Expression of targeted receptors will be monitored by flow cytometry. Clinically developed compounds that could inhibit calprotectin effects will be tested in vitro. |
Countries
France
Contacts
PRINCIPAL_INVESTIGATORMichaela FONTENAY, PhD
Assistance Publique - Hôpitaux de Paris
STUDY_DIRECTOREric SOLARY, MD
Gustave Roussy Institut
Outcome results
None listed