Stem cell origin of myelodysplastic syndromes

Abstract

Myelodysplastic syndromes (MDS) are common hematologic disorders that are characterized by decreased blood counts due to ineffective hematopoiesis. MDS is considered a 'preleukemic' disorder linked to a significantly elevated risk of developing an overt acute leukemia. Cytopenias can be observed in all three myeloid lineages suggesting the involvement of multipotent, immature hematopoietic cells in the pathophysiology of this disease. Recent studies using murine models of MDS as well as primary patient-derived bone marrow samples have provided direct evidence that the most immature, self-renewing hematopoietic stem cells (HSC), as well as lineage-committed progenitor cells, are critically altered in patients with MDS. Besides significant changes in the number and distribution of stem as well as immature progenitor cells, genetic and epigenetic aberrations have been identified, which confer functional changes to these aberrant stem cells, impairing their ability to proliferate and differentiate. Most importantly, aberrant stem cells can persist and further expand after treatment, even upon transient achievement of clinical complete remission, pointing to a critical role of these cells in disease relapse. Ongoing preclinical and clinical studies are particularly focusing on the precise molecular and functional characterization of aberrant MDS stem cells in response to therapy, with the goal to develop stem cell-targeted strategies for therapy and disease monitoring that will allow for achievement of longer-lasting remissions in MDS.

IL8-CXCR2 pathway inhibition as a therapeutic strategy against MDS and AML stem cells

“…Leukemia-initiating stem cells including preleukemic stem cells have been shown to persist even during morphologic remissions after these treatments and have to be targeted for future curative approaches. 1,2,8,9,20,41 It has been shown that leukemia-initiating cells can reside in different phenotypic stem and progenitor compartments at relatively low frequencies and are associated with transcription factor alterations that result in pathogenic transcriptional changes. [2][3][4][5][6][7][11][12][13]32,[42][43][44] Thus, to uncover newer stem cell-directed targets, we conducted a transcriptomic analysis on rigorously defined stem and progenitor populations in AML and MDS in comparison with their respective healthy counterparts.…”

“…[1][2][3][4][5][6][7][8][9] Despite the use of poly-chemotherapy and the development of newer agents, clinical outcome remains poor. The disease course is frequently characterized by relapse or failure to achieve durable remission, indicating that current treatment regimens do not target the cancer-initiating cells.…”

TET2 expression level and 5-hydroxymethylcytosine are decreased in refractory cytopenia of childhood

“…Myelodysplastic syndromes (MDS) are clonal disorders that arise from genetic and/or epigenetics damage in hematopoietic stem cells [1]. MDS are clinically heterogeneous characterized by varying degrees of cytopenias and a high risk of progression to acute myeloid leukemia (AML) [2,3].…”

KIT D816V–mutated bone marrow mesenchymal stem cells in indolent systemic mastocytosis are associated with disease progression

“…4 In parallel, involvement of a multipotent CD34 1 /CD38 2 HPC has also been demonstrated in other myeloproliferative neoplasms (MPNs), myelodysplastic syndromes (MDSs), [17][18][19] and acute myeloid leukemia. 20,21 Moreover, the AHNMD cells from SM-AHNMD patients often carry the KIT D816V mutation, [22][23][24] supporting a common clonal origin for both disease components in an HPC with multilineage potential.…”