Stem and progenitor cells in myelodysplastic syndromes show aberrant stage-specific expansion and harbor genetic and epigenetic alterations

Will, Britta; Zhou, Li; Vogler, Thomas O.; Ben-Neriah, Susanna; Schinke, Carolina; Tamari, Roni; Yu, Yiting; Bhagat, Tushar D.; Bhattacharyya, Sanchari; Barreyro, Laura; Heuck, Christoph; Mo, Yonkai; Parekh, Samir; McMahon, Christine M.; Pellagatti, Andrea; Boultwood, Jacqueline; Montagna, Cristina; Silverman, Lewis B.; Maciejewski, Jaroslaw P.; Greally, John M.; Ye, B. Hilda; List, Alan F.; Steidl, Christian; Steidl, Ulrich; Verma, Amit

doi:10.1182/blood-2011-12-399683

Cited by 199 publications

(259 citation statements)

References 36 publications

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“…We have shown that the relative distribution of these myeloid progenitor populations does not change with age (30). A recent study has shown a relative increase in CMP frequency in MDS (13). We find that low risk MDS bone marrow exhibits alterations in myeloid progenitor distribution, with significant reduction of GMP frequency in low risk MDS compared with normal controls (P < 10 −13 ) and non-MDS bone marrow disorders exhibiting at least one cytopenia ("Other GMP"; P < 10 −10 ) ( Fig.…”

Section: Resultsmentioning

confidence: 56%

“…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).…”

mentioning

confidence: 99%

“…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 initiate the disease itself.…”

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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.

240

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: 56%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

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.

240

259

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“…When viewed from the perspective of increased GMP frequency and its relation to pancytopenia, the B-myb KO phenotype is remarkably similar to that seen in patients with high-risk myelodisplastic syndrome (MDS) (52,53), a group of blood disorders that are characterized by cytopenias that arise due to ineffective hematopoiesis and often progress to acute meylogenous leukemia. MYBL2 is expressed at 20-30% of normal levels in CD34 + cells of ∼65% of MDS cases, irrespective of karyotype (46,54).…”

Section: Discussionmentioning

confidence: 96%

B- myb is an essential regulator of hematopoietic stem cell and myeloid progenitor cell development

Baker

Ma’ayan

Lieu

et al. 2014

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

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The B-myb (MYBL2) gene is a member of the MYB family of transcription factors and is involved in cell cycle regulation, DNA replication, and maintenance of genomic integrity. However, its function during adult development and hematopoiesis is unknown. We show here that conditional inactivation of B-myb in vivo results in depletion of the hematopoietic stem cell (HSC) pool, leading to profound reductions in mature lymphoid, erythroid, and myeloid cells. This defect is autonomous to the bone marrow and is first evident in stem cells, which accumulate in the S and G 2 /M phases. B-myb inactivation also causes defects in the myeloid progenitor compartment, consisting of depletion of common myeloid progenitors but relative sparing of granulocyte-macrophage progenitors. Microarray studies indicate that B-myb-null LSK + cells differentially express genes that direct myeloid lineage development and commitment, suggesting that B-myb is a key player in controlling cell fate. Collectively, these studies demonstrate that B-myb is essential for HSC and progenitor maintenance and survival during hematopoiesis. myeloipiesis | myelodisplastic syndrome

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Acute Myeloid Leukemia Stem Cells—Updates and Controversies

Chung

Park

2014

Cancer Stem Cells

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Stem and progenitor cells in myelodysplastic syndromes show aberrant stage-specific expansion and harbor genetic and epigenetic alterations

Cited by 199 publications

References 36 publications

Hematopoietic stem cell and progenitor cell mechanisms in myelodysplastic syndromes

Hematopoietic stem cell and progenitor cell mechanisms in myelodysplastic syndromes

B- myb is an essential regulator of hematopoietic stem cell and myeloid progenitor cell development

Acute Myeloid Leukemia Stem Cells—Updates and Controversies

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