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[9]
normal hematopoiesis and might also induce malignant transformations . The pathomechanism of
S100A8/A9 in MDS points towards an inflammasome and pyroptosis driven development of clinically
[54]
relevant phenotypes . S100A9 leads to enhanced oxidative stress while activating the inflammasome,
enhancing the proinflammatory signaling that fuels the proliferative and mutagenic effect, and opening a
therapeutic window.

DISEASES CAUSING INFLAMMATION IN THE BONE MARROW NICHE
Further studies looking specifically at the different cell types composing the niche focused on
myeloproliferative disorders, namely myeloproliferative neoplasms such as JAK2 V617F and TPO drove [55,56] ,
acute myeloid leukemia [57,58] , and chronic myeloid leukemia .
[59]
Inflammation causes “neuropathy” in the bone marrow of multiple malignancies such as acute myeloid
leukemia and other myeloproliferative neoplasms. The constitutively active inflammatory status disrupts the
interaction of the glial cells with mesenchymal stromal cells, leading to full-blown leukemia, MPN, or bone
marrow fibrosis [55,57,59] . Thus, dysregulation of the neural niche is an appealing therapeutic target that might
affect inflammation; a Beta3-adrenergic agonist, neural-glial protection, and IL-1R antagonist are being
studied [55,57,59] . Fibrosis in the microenvironment in the bone marrow represents the most massive
remodeling of the milieu and recognizes both solid and hematological underlying disease in addition to
metabolic disease, immune-related disorders, infections, and aging [60,61] . In more detail, a more robust side
population of Gli1 cells, responsible for this remodeling of the bone that aligns the bone in normal
pos
conditions, can also be found in proximity to the vascular localization [62,63] . By inducing fibrosis in animal
models, these cells are activated from the usual niche and suddenly are expanded in bone marrow fibrosis.
Notably, ablation of Gli1 cells rescues bone marrow fibrosis.
pos
Thus, the underlying processes of inflammation seem to characterize the pre-fibrotic phase, and, in the
HSC, there is an increase of inflammatory signaling toward NF-κB signaling, TNF-α, and through the
[64]
activation of JAK-STAT . Interestingly, in the early stages when fibrosis starts, the signature of
inflammation as a disease initiator is also present. On RNA sequencing at a single cell level of the non-
hematopoietic niche, four different populations have been found: mesenchymal stromal cells (MSC-1/2)
and Schwan cell progenitors constituting the neuronal niche, as glial cells, the osteolinear cells, and the
vascular cells . Focusing on the MSC-1/2, it has been shown that they are functionally reprogrammed in
[64]
fibrosis, losing their conventional markers profile; in addition, they seem to express fewer MSC markers,
ultimately losing their function of hematopoiesis support, and they start making collagen. Therefore, only
two of the different populations of cells are responsible for this massive remodeling of the bone marrow
through extracellular matrix synthesis, collagens, secretion factors, and neo-angiogenesis . In the profile of
[64]
secreted factors, the spread of S100A8/9 in myeloproliferative neoplasms and myelofibrosis with a massive
increase of S100A8 in patient plasma has been reported. This increase could correlate, based on the above,
with the deficient phenotype of RPS14 for MDS. In other words, the alterations observed in ribosomal gene
expression and translation-related gene expression in HSC of 5q- syndrome are a consequence of the
haploinsufficiency of RPS14. These aberrations can compromise the biogenesis of the ribosome and
consequent reduction of the translation efficiency of proteins . In this frame of thinking, reactive oxygen
[65]
species can be produced either because of somatic mutations or due to S100A8 or S100A9. As alarmins
molecules, they are shed during pyroptosis and tip the balance between immune and inflammatory
responses [51,64-66] . These events ultimately induce caspase 1 activation, which in turn drives a plethora of
downstream consequences such as IL-1β- and IL-18-mediated cell damages [51,64-66] . These underlying
mechanisms are distinctive of MDS and represent novel, promising Achille’s heels to improve
[65]
hematopoiesis in myelodysplastic syndromes [51,64-66] .