The molecular signature of MDS stem cells supports a stem-cell origin of 5q− myelodysplastic syndromes

Nilsson, Lars; Edén, Patrik; Olsson, Elin; Månsson, Robert; Åstrand-Grundström, Ingbritt; Strömbeck, Bodil; Theilgaard‐Mönch, Kim; Anderson, Kristina; Hast, Robert; Hellström‐Lindberg, Eva; Samuelsson, Jan; Bergh, Gösta; Nerlov, Claus; Johansson, Bertil; Sigvardsson, Mikael; Borg, Åke; Jacobsen, Sten Eirik W.

doi:10.1182/blood-2007-03-079368

Cited by 108 publications

(99 citation statements)

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“…Previously, it has been shown that the HSC compartment in MDS is enriched for cytogenetically abnormal cells, including in two MDS samples with monosomy 7 (10,11,13). We evaluated three MDS samples harboring a clonal monosomy 7 cytogenetic abnormality.…”

Section: Resultsmentioning

confidence: 99%

“…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)(11)(12)(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).…”

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confidence: 99%

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Hematopoietic stem cell and progenitor cell mechanisms in myelodysplastic syndromes

Pang

Pluvinage

Price

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

246

259

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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...

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Hematopoietic stem cell and progenitor cell mechanisms in myelodysplastic syndromes

Pang

Pluvinage

Price

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

246

259

View full text Add to dashboard Cite

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“…HSC (23,24). Abnormal in vitro hematopoietic colony formation has been observed (24,25), but interpretation of in vitro colony assays has been complicated by the growth of contaminating normal hematopoietic progenitors that are not part of the malignant clone.…”

Section: Discussionmentioning

confidence: 99%

Transplantation of a myelodysplastic syndrome by a long-term repopulating hematopoietic cell

Chung¹,

Choi²,

Slape³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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The myelodysplastic syndromes (MDS) comprise a group of premalignant hematologic disorders characterized by ineffective hematopoiesis, dysplasia, and transformation to acute myeloid leukemia (AML). Although it is well established that many malignancies can be transplanted, there is little evidence to demonstrate that a premalignant disease entity, such as MDS or colonic polyps, can be transplanted and subsequently undergo malignant transformation in vivo. Using mice that express a NUP98-HOXD13 (NHD13) transgene in hematopoietic tissues, we show that a MDS can be transplanted to WT recipients. Recipients of the MDS bone marrow displayed all of the critical features of MDS, including peripheral blood cytopenias, dysplasia, and transformation to AML. Even when transplanted with a 10-fold excess of WT cells, the NHD13 cells outcompeted the WT cells over a 38-week period. Limiting-dilution experiments demonstrated that the frequency of the cell that could transmit the disease was Ϸ1/6,000 -1/16,000 and that the MDS was also transferable to secondary recipients as a premalignant condition. Transformation to AML in primary transplant recipients was generally delayed (46 -49 weeks after transplant); however, 6 of 10 secondary transplant recipients developed AML. These findings demonstrate that MDS originates in a transplantable, premalignant, long-term repopulating, MDS-initiating cell.hematopoiesis ͉ HOX gene ͉ leukemia ͉ transplant ͉ NUP98

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“…Furthermore, for the 5q‐ syndrome, it has been shown that, even at an early time point in the course of the disease, the normal HSC compartment has almost completely been replaced with clonally expanded stem cells that are positive for the cytogenetic 5q‐ aberration (Nilsson et al , 2007). Woll et al (2014) provided evidence of distinct cancer stem cells (CSCs) in MDS by tracing all identified somatic mutations in the bulk BM back to the immunophenotypically defined Lin‐CD34 + CD38 − CD90 + stem cell.…”

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confidence: 99%

Unravelling the relevance of CLEC12A as a cancer stem cell marker in myelodysplastic syndrome

et al. 2016

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SummaryEvidence of distinct disease propagating stem cells in myelodysplastic syndrome (MDS) has emerged in recent years. However, immunophenotypic characterization of these cancer stem cells remains sparse. In acute myeloid leukaemia (AML), we have previously described aberrant expression of the C‐type lectin domain family 12, member A (CLEC12A) as a stable and reliable marker of leukaemia blasts and as a tool for assessing minimal residual disease. Furthermore, CLEC12A has been proposed as a promising marker of leukaemic stem cells in AML. The role of CLEC12A in MDS, however, remains to be elucidated. In this study, we found CLEC12A aberrantly expressed on the CD34+ CD38− cell compartment in 71% (22/31) of MDS patients, distributed across all Revised International Prognostic Scoring System risk groups. We showed that the CD34+ CD38− CLEC12A+ cells were indeed malignant and possessed functional stem cell properties in the long‐term colony‐initiating cell assay. As opposed to reported findings in AML, we showed that cancer stem cells from MDS samples derived from both CLEC12A positive and negative CD34+ CD38− subpopulations. Due to the absence of CLEC12A on normal haematopoietic stem cells, CLEC12A stem cell immunophenotyping may contribute to diagnosing and monitoring MDS patients and could furthermore add knowledge about disease propagating cells in MDS.

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The molecular signature of MDS stem cells supports a stem-cell origin of 5q− myelodysplastic syndromes

Cited by 108 publications

References 50 publications

Hematopoietic stem cell and progenitor cell mechanisms in myelodysplastic syndromes

Hematopoietic stem cell and progenitor cell mechanisms in myelodysplastic syndromes

Transplantation of a myelodysplastic syndrome by a long-term repopulating hematopoietic cell

Unravelling the relevance of CLEC12A as a cancer stem cell marker in myelodysplastic syndrome

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