Transcription patterning of uncoupled proliferation and differentiation in myelodysplastic bone marrow with erythroid-focused arrays

Lee, Y. Terry; Miller, Lance D.; Gubin, Alexander N.; Makhlouf, Fairouz; Wojda, Urszula; Barrett, A. John; Liu, Edison T.; Miller, Jeffery L.

doi:10.1182/blood.v98.6.1914

Cited by 32 publications

(21 citation statements)

References 26 publications

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“…21 In our study, refractory anemia with excess blasts with erythroid predominance comprised a significantly higher proportion of cases with a poor-risk karyotype, such as -7, -7q, -5, or a complex karyotype, compared to the control group, and these cases showed a poor overall survival irrespective of the blast ranges. We further demonstrated overall survival difference by International Prognostic Scoring System risk groups in these patients, where cytogenetic risk is incorporated into the scoring system.…”

Section: Discussionmentioning

confidence: 88%

Erythroid-predominant myelodysplastic syndromes: enumeration of blasts from nonerythroid rather than total marrow cells provides superior risk stratification

et al. 2008

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In the FAB (French-American-British) and WHO (World Heath Organization) classifications, the blasts in erythroleukemia (M6a) are enumerated from the marrow nonerythroid rather than the total-nucleated cells. However, the method for blast calculation in erythroid-predominant myelodysplastic syndrome (erythroblastsZ50%) is not specified either in the FAB or WHO classifications. We retrieved the files of 74 erythroid-predominant myelodysplastic syndrome patients (17% of all myelodysplastic syndrome) and 192 myelodysplastic syndrome controls (erythroblastso50%). In erythroid-predominant myelodysplastic syndrome, by enumerating blasts from marrow nonerythroid cells rather than from total nucleated cells, 41 of 74 (55%) cases would be upgraded, either by disease subcategory or International Prognostic Scoring System. Importantly, the patients with o5% blasts demonstrated a superior survival to patients with Z5% blasts (P ¼ 0.002); this distinction was lost when blasts were calculated from total-nucleated cells. Of cases with Z5% blasts, cytogenetics rather than blast count correlated with survival. We conclude that in erythroid-predominant myelodysplastic syndrome, blast calculation as a proportion of marrow nonerythroid rather than total nucleated cells can better stratify patients into prognostically relevant groups.

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Section: Discussionmentioning

confidence: 88%

Erythroid-predominant myelodysplastic syndromes: enumeration of blasts from nonerythroid rather than total marrow cells provides superior risk stratification

et al. 2008

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“…Recently, we and others 11,[15][16][17][18][19][20][21] have shown that microarray analysis can provide sufficient data to detect genes or gene patterns associated with alterations of specific cellular pathways or signal cascades in tumor cells. For example, several new genes regulated by p53 have been identified that are important in p53-induced cell cycle arrest.…”

Section: Discussionmentioning

confidence: 99%

Characterization of gene expression of CD34+ cells from normal and myelodysplastic bone marrow

Hofmann

Vos

Komor

et al. 2002

Blood

219

150

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Gene patterns of expression in purified CD34 ؉ bone marrow cells from 7 patients with low-risk myelodysplastic syndrome (MDS) and 4 patients with high-risk MDS were compared with expression data from CD34 ؉ bone marrow cells from 4 healthy control subjects. CD34 ؉ cells were isolated by magnetic cell separation, and high-density oligonucleotide microarray analysis was performed. For confirmation, the expression of selected genes was analyzed by real-time polymerase chain reaction. Class membership prediction analysis selected 11 genes. Using the expression profile of these genes, we were able to discriminate patients with low-risk from patients with high-risk MDS and both patient groups from the control group by hierarchical clustering (Spearman confidence). The power of these 11 genes was verified by applying the algorithm to an unknown test set containing expression data from 8 additional patients with MDS (3 at low risk, 5 at high risk). Patients at low risk could be distinguished from those at high risk by clustering analysis. In low-risk MDS, we found that the retinoic-acid-induced gene (RAI3), the radiation-inducible, immediateearly response gene (IEX1), and the stress-induced phosphoprotein 1 (STIP1) were down-regulated. These data suggest that CD34 ؉ cells from patients with low-risk MDS lack defensive proteins, resulting in their susceptibility to cell damage.

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“…To determine whether the capacity to generate RBC was impaired in non-deleted clones in the bone marrow of 5q(del) patients, we selected a 100% cytogenetically nondeleted population by LDA and assessed its erythroid + cell from the nondeleted clone generated 3.7×10 5 RBC, compared to 1.77×10 6 for one CD34 + cell from the healthy control and 2.02×10 4 for one CD34 + 5q(del) clone cell. Overall, residual non-deleted clones in MDS patients generated 18 times more RBC than 5q(del) clone, but five times fewer RBC than the healthy clone.…”

Section: Non-deleted Erythropoiesis In 5q(del) Patientsmentioning

confidence: 99%

“…MDS are thought to be due to acquired clonal anomalies of hematopoietic stem cells, 4 in particular to a defect in the differentiation of these cells. 5,6 This is the rationale that underpins current treatment. 7 However, the lack of a complete in vitro model for erythropoiesis that includes enucleation means that the pathophysiology of anemia remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Unimpaired terminal erythroid differentiation and preserved enucleation capacity in myelodysplastic 5q(del) clones: a single cell study

Garderet¹,

Kobari²,

Mazurier³

et al. 2009

Haematologica

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BackgroundAnemia is a characteristic of myelodysplastic syndromes, such as the rare 5q-syndrome, but its mechanism remains unclear. In particular, data are lacking on the terminal phase of differentiation of erythroid cells (enucleation) in myelodysplastic syndromes. Design and MethodsWe used a previously published culture model to generate mature red blood cells in vitro from human hematopoietic progenitor cells in order to study the pathophysiology of the 5q-syndrome. Our model enables analysis of cell proliferation and differentiation at a single cell level and determination of the enucleation capacity of erythroid precursors. ResultsThe erythroid commitment of 5q(del) clones was not altered and their terminal differentiation capacity was preserved since they achieved final erythroid maturation (enucleation stage). The drop in red blood cell production was secondary to the decrease in the erythroid progenitor cell pool and to impaired proliferative capacity. RPS14 gene haploinsufficiency was related to defective erythroid proliferation but not to differentiation capacity. ConclusionsThe 5q-syndrome should be considered a quantitative rather than qualitative bone marrow defect. This observation might open the way to new therapeutic concepts.Key words: myelodysplastic syndrome, 5q-syndrome, erythroid differentiation, enucleation. (del) clones: a single cell study. Haematologica. 2010; 95:398-405. doi:10.3324/haematol.2009 This is an open-access paper. Citation: Garderet L, Kobari L, Mazurier C, De Witte C, Giarratana M-C, Pérot C, Gorin NC, Lapillonne H, and Douay L. Unimpaired terminal erythroid differentiation and preserved enucleation capacity in myelodysplastic 5qUnimpaired terminal erythroid differentiation and preserved enucleation capacity in myelodysplastic 5q(del) clones: a single cell study

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Transcription patterning of uncoupled proliferation and differentiation in myelodysplastic bone marrow with erythroid-focused arrays

Cited by 32 publications

References 26 publications

Erythroid-predominant myelodysplastic syndromes: enumeration of blasts from nonerythroid rather than total marrow cells provides superior risk stratification

Erythroid-predominant myelodysplastic syndromes: enumeration of blasts from nonerythroid rather than total marrow cells provides superior risk stratification

Characterization of gene expression of CD34+ cells from normal and myelodysplastic bone marrow

Unimpaired terminal erythroid differentiation and preserved enucleation capacity in myelodysplastic 5q(del) clones: a single cell study

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