Stem and progenitor cell alterations in myelodysplastic syndromes
#MMPMID28159737
Shastri A
; Will B
; Steidl U
; Verma A
Blood
2017[Mar]; 129
(12
): 1586-1594
PMID28159737
show ga
Recent studies have demonstrated that myelodysplastic syndromes (MDSs) arise from
a small population of disease-initiating hematopoietic stem cells (HSCs) that
persist and expand through conventional therapies and are major contributors to
disease progression and relapse. MDS stem and progenitor cells are characterized
by key founder and driver mutations and are enriched for cytogenetic alterations.
Quantitative alterations in hematopoietic stem and progenitor cell (HSPC) numbers
are also seen in a stage-specific manner in human MDS samples as well as in
murine models of the disease. Overexpression of several markers such as
interleukin-1 (IL-1) receptor accessory protein (IL1RAP), CD99, T-cell
immunoglobulin mucin-3, and CD123 have begun to differentiate MDS HSPCs from
healthy counterparts. Overactivation of innate immune components such as
Toll-like receptors, IL-1 receptor-associated kinase/tumor necrosis factor
receptor-associated factor-6, IL8/CXCR2, and IL1RAP signaling pathways has been
demonstrated in MDS HSPCs and is being targeted therapeutically in preclinical
and early clinical studies. Other dysregulated pathways such as signal transducer
and activator of transcription 3, tyrosine kinase with immunoglobulinlike and
EGF-like domains 1/angiopoietin-1, p21-activated kinase, microRNA 21, and
transforming growth factor ? are also being explored as therapeutic targets
against MDS HSPCs. Taken together, these studies have demonstrated that MDS stem
cells are functionally critical for the initiation, transformation, and relapse
of disease and need to be targeted therapeutically for future curative strategies
in MDSs.
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