ERIC SOLARY (PARIS)
SIMILARITIES / DISPARITIES BETWEEN SARS-COV-2 INFECTION AND CHRONIC
MYELOID MALIGNANCIES
I
NSERM U1287 & Department of Clinical Hematology, Gustave Roussy Cancer Center, Villejuif,
France
Chronic myeloid malignancies are clonal diseases of the hematopoietic stem cell (HSC) in
which mature cells of the clone contribute to disease development, as demonstrated initially
in a mouse model of chronic myeloid leukemia. In this model, BCR/ABL tyrosine kinase activity
promotes overproduction of interleukin-6 (IL-6) by mature myeloid cells. In turn, IL-6 skews
immature cell differentiation toward the myeloid lineage.1 Importantly, IL-6 neutralization
blocks disease installation and progression.2 Similarly, TET2 gene mutation, a common
somatic event in myeloid malignancies, compromises the regulation of IL6 and MIF gene
expression in monocytes and macrophages.3 Finally, in myelodysplastic syndromes, cellular
dysplasia can be enforced by alarmins such as S100A8 and S100A9 released by mature, though
dysplastic myeloid cells.4-7 These observations position cytokine-and chemokine-dependent
feedforward loops between mature cells and HSCs as potential therapeutic targets in chronic
myeloid malignancies.
Similar interactions could account for the deregulation of blood myeloid cells mediating a
pathogenic innate immune response to the coronavirus disease 2019 (COVID-19) caused by
SARS-CoV-2. By performing high dimensional flow cytometry and single cell RNA sequencing
of COVID-19 patient peripheral blood cells, we detected the disappearance of non-classical
CD14LowCD16High monocytes, the accumulation of HLA-DRLow classical monocytes, and the
release of massive amounts of calprotectin (S100A8/S100A9 heterodimer) as hallmarks of
severe COVID-19. Immature CD10LowCD101-CXCR4+/- neutrophils with an immuno-suppressive
profile accumulated as well in blood and lungs, suggesting emergency
myelopoiesis. Calprotectin plasma level and a routine flow cytometry assay that measures the
fraction of non-classical monocytes in the blood could stratify COVID-19 patients to guide their
clinical management.8
Similarities and discrepancies between chronic myeloid malignancies and severe COVID-19
will be discusses, as well as the reasons that could explain the severity of COVID-19 in patients
with a hematological malignancies and the potential interest of therapeutic strategies
targeting calprotectin to alleviate these diseases.
References
1. Reynaud D, et al. IL-6 controls leukemic multipotent progenitor cell fate and contributes to chronic
myelogenous leukemia development. Cancer Cell. 2011;20:661-73.
2. Welner RS, et al. Treatment of chronic myelogenous leukemia by blocking cytokine alterations found
in normal stem and progenitor cells. Cancer Cell. 2015;27:671-81.
3. Zhang Q, et al. Tet2 is required to resolve inflammation by recruiting Hdac2 to specifically repress
IL-6. Nature. 2015;525:389-393.
4. Chen X, et al. Induction of myelodysplasia by myeloid-derived suppressor cells. J Clin Invest.
2013;123:4595-611.
5. Schneider RK, et al. Rps14 haploinsufficiency causes a block in erythroid differentiation mediated
by S100A8 and S100A9. Nat Med. 2016;22:288-97.