Page 39 - Read Online

Page 2 of 14 Tosato et al. J Cancer Metastasis Treat 2021;7:52 https://dx.doi.org/10.20517/2394-4722.2021.120

affecting at least 10% of bone marrow cells belonging to one or more than one cell lineages. Based on the
combination of morphologic cell abnormalities and cytogenetic abnormalities, the 2016 revised
classification of the World Health Organization has distinguished six MDS subtypes: MDS with a single-
lineage dysplasia, MDS with multilineage dysplasia, MDS with ring sideroblasts and single-lineage dysplasia
or multilineage dysplasia, MDS with isolated deletion of the chromosome 5q [del(5q)], MDS with excess
blasts type 1 or type 2, and unclassifiable MDS. Myelodysplastic-myeloproliferative neoplasms (MPN) are a
group of myeloid neoplasms with clinical, laboratory, and morphologic features that overlap those of
[1]
MDS .
In health, hematopoiesis relies on interactions between the hematopoietic cells and surrounding non-
hematopoietic “stromal” cells for survival and function. These interactions occur in certain
microenvironments, called niches, through cell-to-cell association, vesicular particles, and soluble mediators
acting systemically or at short-distance. The self-renewing hematopoietic stem cells (HSC), at the top of the
hematopoietic hierarchy, are dependent on their niches for survival. Mutant hematopoietic cells in MDS,
like normal HSC that have self-renewing potential, can also rely on niche factors for their survival and
expansion. In some cases, niches can also promote MDS resistance to treatment.

Recent advances in single-cell genomics have provided an unprecedented appreciation of the diversity of
the non-hematopoietic cell populations that reside in the bone marrow and have permitted to infer
functional capabilities of hematopoietic cell niches. These advances, combined with a better understanding
of genetic lesions in MDS, provide an opportunity for outlining potential roles of niches in pathologic
hematopoiesis. Despite improved understanding of the pathogenesis of MDS, therapeutic advances have
been limited since 2005 when FDA approved lenalinomide for patients with low or intermediate risk MDS
with chromosome 5q deletion. Bone marrow transplantation remains the only curative treatment for some
patients. Therefore, abnormal niches provide an opportunity for discovery of new treatments. Here, we
summarize our understanding of the bone marrow niches in health and their abnormalities in myeloid
malignancies, particularly in MDS. This seems an important step towards development of therapies
targeting the niche rather than the mutant hematopoietic cells.

BONE MARROW NICHES IN HEALTH
Endothelial cells, mesenchymal lineage cells, and sympathetic neuronal cells are the major non-
hematopoietic cell components of the normal adult bone marrow in mice and humans. Studies in the
mouse have concluded that most HSC reside in proximity to the blood vessels. Consistently, the HSC niches
have been provisionally defined based on their relationship of the vessels and more broadly on their
anatomical location within the bone. The inner core of the bone marrow (the central niche) comprises >
90% of the bone marrow volume and contains 85% of HSC, whereas the endosteal niche at the periphery of
the bone marrow near the bone harbors the remaining 15% HSC . Thus, the endosteal niche is relatively
[2,3]
enriched with HSC.

Sinusoids, arterioles, and vessels that connect sinusoids and arterioles are the types of blood vessels
identified morphologically in the bone marrow [Table 1]. Sinusoids are the most abundant vascular system,
accounting for 30% ± 5% of the bone marrow volume. These vessels form a highly branched and fenestrated
capillary network where the individual vessels are regularly spaced by 46 ± 1 µm and are distributed
[4]
throughout the length of the long bones . Arterioles, which comprise only 1.2% ± 0.1% of bone marrow
volume, are mostly present near the bone where they are fed by arteries penetrating the bone cortex .
[4]
Arterioles and sinusoids are connected by transition zone capillaries that are in the endosteal niche, mostly
at the bone metaphysis . Based on high-level expression of the surface markers endomucin and
[5]