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Page 6 of 12 Solimando et al. J Cancer Metastasis Treat 2022;8:9 https://dx.doi.org/10.20517/2394-4722.2021.166

sustained anemia based on inflammatory cytokines throughout the body, affecting macrophages in the bone
marrow [44-47] . MDS also constitutes a condition associated with cytopenia, particularly in anemia, in which
hematopoietic stem and progenitor cells acquire a mutation that leads to a clonal expansion of immature
cells; additionally, in the bone marrow, variable grades of dysplasia are present, with various degrees of
cytopenia . Mathematical models also uncovered the mechanisms of HSC loss, highlighting the relevance
[48]
[49]
of impaired division, increased cell death, displacement, and abnormal differentiation . Nonetheless, the
stem cells that seem to be lost in pre-clinical models, at least during chronic infections, are primarily
[49]
damaged by an aberrant terminal differentiation . The model is that typically hematopoietic stem cells sit
right up close to the CXCL12-abundant reticular cells, but in the setting of IFN-γ stimulation they may
upregulate Bst2, which pulls them over to a different part of the niche that E-selectin marks, and this may
[50]
release them from quiescence and let them divide .
Remarkably, inflammation in the bone marrow already primes HSCs for malignancy; in fact, a normal HSC
is under the stress of persistent chronic inflammation due to multiple phenomena, such as chronic diseases
and aging. Therefore, toll-like receptor (TLR) signaling plays a role in mediating the inflammatory stress,
[48]
making the HSC more susceptible to acquiring mutations correlated to MDS . Higher inflammatory status
is also observed, due to a higher secretion of proinflammatory cytokines from the HSC, affecting the
microenvironment trapped into a vicious cycle that feeds on itself.

Established animal models based on deficient ribosomal protein S14 (RPS14) phenotype allow studying the
level of myelodysplastic anemia, and, while harvesting stem cells from RPS14-deficient mice, they are not
able to differentiate into blood cells. The underlying cause for the break in the erythroid differentiation is
most likely related to increased levels of S100A8 and S100A9 proteins, both related to the immune response
and inflammation via TLR4 and NF-κB activation, being a potential therapeutic target both in MDS and in
chronic inflammation. S100A8 expression is found in the erythroblastic island in RPS14-deficient mice,
[51]
where increased S100A8 also induces P53-dependent differentiation block activation . Therefore,
inflammation can be a target due to the paradigmatic role of S100A8 as an essential factor for the erythroid
differentiation while being a potential therapeutic target in MDS patients with anemia; furthermore,
[52]
increased S100A8 expression has also been observed in the endosteal and perivascular niche . Hence, there
is a need for a close investigation of S100A8 expression in an endosteal niche, the mesenchymal component
[53]
of the endosteal milieu of MDS, and bone marrow failure such as Schwachman-Diamond syndrome . By
performing immunohistochemistry staining, CD271 highlights the mesenchymal stroma compartment and
allows stratifying patients with low-risk MDS according to S100A8 low and high expressors while
identifying a worse survival for patients who express high S100A8 levels . These individuals have a higher
[53]
frequency of leukemic evolution, potentially showing that inflammation can represent a trigger in this
disease, priming the hematopoietic cells for transformation depending on the microenvironment.

By isolating the stromal cells and co-culturing them with normal HSPCs, upon upregulation of S100A8 on
the stromal cells, a decreased hematopoietic support was observed, with downregulation of CXCL12; a lack
of quiescence was also obtained, with cell cycle activation and proliferation along with increased apoptosis
[53]
in HSPCs . Based on these pieces of evidence, inflammation represents a target for disease, as exemplified
by the expression of S100A8 in the endosteal and perivascular niche, driving a loss of ordinary
hematopoietic support and leading to genotoxic stress, sustaining malignant hematopoiesis and priming a
more mutagenic environment, in the context of senescence.

The multiple inflammatory targets described affect the environment in the bone marrow, specifically
leading to anemia, while the inflammation close to the endosteal and perivascular niche seems to affect