Hematopoietic stem cell and progenitor cell mechanisms in myelodysplastic syndromes

Abstract

Myelodysplastic syndromes (MDS) are a group of disorders characterized by variable cytopenias and ineffective hematopoiesis. Hematopoietic stem cells (HSCs) and myeloid progenitors in MDS have not been extensively characterized. We transplanted purified human HSCs from MDS samples into immunodeficient mice and show that HSCs are the disease-initiating cells in MDS. We identify a recurrent loss of granulocyte-macrophage progenitors (GMPs) in the bone marrow of low risk MDS patients that can distinguish low risk MDS from clinical mimics, thus providing a simple diagnostic tool. The loss of GMPs is likely due to increased apoptosis and increased phagocytosis, the latter due to the up-regulation of cell surface calreticulin, a prophagocytic marker. Blocking calreticulin on low risk MDS myeloid progenitors rescues them from phagocytosis in vitro. However, in the high-risk refractory anemia with excess blasts (RAEB) stages of MDS, the GMP population is increased in frequency compared with normal, and myeloid progenitors evade phagocytosis due to up-regulation of CD47, an antiphagocytic marker. Blocking CD47 leads to the selective phagocytosis of this population. We propose that MDS HSCs compete with normal HSCs in the patients by increasing their frequency at the expense of normal hematopoiesis, that the loss of MDS myeloid progenitors by programmed cell death and programmed cell removal are, in part, responsible for the cytopenias, and that up-regulation of the "don't eat me" signal CD47 on MDS myeloid progenitors is an important transition step leading from low risk MDS to high risk MDS and, possibly, to acute myeloid leukemia.myelodysplasia | blood disorders | aging | monosomy 7 | cancer stem cell T he World Health Organization (WHO) defines myelodysplastic syndromes (MDS) as a heterogeneous group of related clonal diseases characterized by variable cytopenias due to ineffective hematopoiesis and increased risk of progression to acute myeloid leukemia (AML) (1-4). To date, functional and diagnostic evaluations of immature hematopoietic cells in MDS have predominantly relied on unpurified or partially purified bone marrow cells (most frequently CD34 + cells; reviewed in ref. 5), which have limited power to identify cell lineage specific alterations. We have taken advantage of the purification of highly enriched HSCs and committed myeloid progenitors (6-9) via fluorescence activated cell sorting (FACS) to characterize hematopoietic subsets in primary MDS patient bone marrow samples with the goal of increasing the understanding of MDS pathogenesis.Recent fluorescence in situ hybridization (FISH) and gene expression data from purified HSCs from 5q-MDS patients have suggested an HSC origin for MDS (10-13). HSCs from MDS patients (MDS HSCs) are relatively resistant to lenalidomide and decitabine treatment, because even patients with cytogenetic remission, as determined by FISH on peripheral blood cells, can maintain a significant MDS HSC burden (12, 13). Nevertheless, HSCs from MDS patients have not been shown to initiat...

How One Thing Led to Another

“…We recently showed that the HSCs in MDS that show a clonal pathogenic chromosomal event such as 5q-or monosomy 7 expand at the expense of normal HSCs, just as we had shown in CML (240). But the progeny of these hypercompetitive HSCs produce progenitors that are phagocytosed, likely to be responsible for the loss in blood of red blood cells and/or granulocytes and/or platelets (240). So MDS is a prototype of preleukemic progression wherein the successful clone has blocked programmed cell death, but its oligolineage progeny, also highly viable, can, in a stage-specific manner, express cell surface calreticulin and are phagocytosed in a calreticulin-dependent event (240).…”

“…Now we knew that it was the "eat me" signal that was expressed on the surface of all AML cells. We showed later that calreticulin was expressed on the surface of the GMP and erythrocyte progenitor cells in the marrow of patients with myelodysplastic syndrome (MDS), and we showed that, as a consequence, their frequency relative to other marrow cells was significantly diminished (240). We recently showed that the HSCs in MDS that show a clonal pathogenic chromosomal event such as 5q-or monosomy 7 expand at the expense of normal HSCs, just as we had shown in CML (240).…”

“…We showed later that calreticulin was expressed on the surface of the GMP and erythrocyte progenitor cells in the marrow of patients with myelodysplastic syndrome (MDS), and we showed that, as a consequence, their frequency relative to other marrow cells was significantly diminished (240). We recently showed that the HSCs in MDS that show a clonal pathogenic chromosomal event such as 5q-or monosomy 7 expand at the expense of normal HSCs, just as we had shown in CML (240). But the progeny of these hypercompetitive HSCs produce progenitors that are phagocytosed, likely to be responsible for the loss in blood of red blood cells and/or granulocytes and/or platelets (240).…”

PUMA promotes apoptosis of hematopoietic progenitors driving leukemic progression in a mouse model of myelodysplasia

“…[1][2][3] Despite their genetic heterogeneity, they share common phenotypic features including low peripheral blood counts (cytopenias) in spite of a hypercellular bone marrow (ineffective hematopoiesis), dysplasia and a variable propensity for transformation to acute myeloid leukemia (AML). 4 Programmed cell death or apoptosis of white blood cells is a common feature, and is thought to contribute to the cytopenias particularly in early stages of the disease.…”

Myelodysplastisches Syndrom, akute Leukämie und Stammzelltransplantation

“…Deren genetische Instabilität ist die Grundlage für den Erwerb einer Vielzahl weiterer Mutationen, die mit dem Verlust der normalen Differenzierungskapazität schließlich funktionell zu einer dysplastischen und ineffektiven Hämatopoese führen [2]. Allerdings findet sich in Kollektiven älterer (>70 Jahre), asymptomatischer Personen bei einem Anteil von bis zu 10 % der Nachweis einer klonal veränderten Hämatopoese, deren klinische Bedeutung gegenwärtig unklar ist [3].…”