Hematopoietic progenitor cells from patients with myelodysplastic syndromes: in vitro colony growth and long-term proliferation

Flores-Figueroa, Eugenia; Gutiérrez-Espı́ndola, Guillermo; Guerrero-Rivera, Susana; Pizzuto-Chávez, J; Mayani, Héctor

doi:10.1016/s0145-2126(98)00176-3

Cited by 33 publications

(24 citation statements)

References 22 publications

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“…Furthermore, our model presented a pattern of graded severity from unilineage to multilineage dysplasia, similar to what is often observed in the clinic in low-risk vs high-risk MDS cases (Figures 3B and S5B). The impaired differentiation and reduced clonogenicity affecting erythroid and multilineage progenitors first, is a very likely correlate of the ineffective hematopoiesis and cytopenias observed in MDS patients, which predominantly affect the erythroid lineage, and consistent with findings in primary MDS cells cultured ex vivo (Flores-Figueroa et al., 1999; Sato et al, 1998). The increased cell death is consistent with findings of apoptotic markers in primary patient BM, which has led to the proposition that apoptosis may be another pathophysiologic mechanism accounting for the cytopenias (Kerbauy and Deeg, 2007).…”

Section: Discussionsupporting

confidence: 74%

Stage-Specific Human Induced Pluripotent Stem Cells Map the Progression of Myeloid Transformation to Transplantable Leukemia

et al. 2017

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SUMMARY Myeloid malignancy is increasingly viewed as a disease spectrum, comprising hematopoietic disorders that extend across a phenotypic continuum ranging from clonal hematopoiesis to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). In this study, we derived a collection of iPSC lines capturing a range of disease stages encompassing preleukemia, low-risk MDS, high-risk MDS and secondary AML. Upon differentiation, we found hematopoietic phenotypes of graded severity and/or stage specificity that together delineate a phenotypic roadmap of disease progression culminating in serially transplantable leukemia. We also show that disease stage transitions, both reversal and progression, can be modeled in this system using genetic correction or introduction of mutations via CRISPR/Cas9, and that this iPSC-based approach can be used to uncover disease stage-specific responses to drugs. Our study therefore provides insight into the cellular events demarcating the initiation and progression of myeloid transformation and a new platform for testing genetic and pharmacological interventions.

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Section: Discussionsupporting

confidence: 74%

Stage-Specific Human Induced Pluripotent Stem Cells Map the Progression of Myeloid Transformation to Transplantable Leukemia

et al. 2017

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“…3 In vitro cultures of hematopoietic progenitors can provide additional useful information for the diagnosis of MDS, since colony formation is poor or absent in most of these patients. 4 Thus, overt marrow dysplasia, clonal cytogenetic abnormality, and reduced in vitro progenitor cell growth allow a conclusive diagnosis of MDS. 1 This combination is, however, found in only some MDS patients, who tend to be those with more advanced disease.…”

Section: Introductionmentioning

confidence: 99%

Flow cytometry evaluation of erythroid and myeloid dysplasia in patients with myelodysplastic syndrome

et al. 2005

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The purpose of this study was to develop a flow cytometric approach to the evaluation of marrow dysplasia in myelodysplastic syndromes (MDS). We first studied a cohort of 103 MDS patients as well as 46 pathological and healthy controls. Flow cytometry data were expressed as percentage of positive cells. Analysis of erythroid cells showed higher proportions of immature cells (Po0.001) and decreased levels of CD71 expression on nucleated red cells (P ¼ 0.02) in MDS. Analysis of myeloid cells showed lower proportions of CD10 þ and higher proportions of CD56 þ granulocytes (Po0.001), and increased ratios of immature to mature cells (P ¼ 0.007). Since no single immunophenotype could accurately differentiate MDS from other conditions, we used discriminant analysis for generating erythroid and myeloid classification functions using combinations of immunophenotypic parameters. These functions were prospectively validated in a testing cohort of 69 MDS patients and 46 pathological controls. A diagnosis of MDS was obtained in 60/69 cases (87%). No false-positive results were noticed among controls. Significant correlations between values of these functions and both degree of morphological dysplasia and the International Prognostic Scoring System were found. These findings indicate that flow cytometry evaluation of marrow dysplasia is feasible and may be useful in the work-up of individual MDS patients.

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“…Typically the bone marrow (BM) of MDS patients is of normal cellularity or is hypercellular but often with a reduced number of primitive progenitors. These include cells able to generate colonies of terminally differentiating myeloid cells directly in semisolid media (colony-forming cells [CFCs]) 3,4 as well as their more primitive precursors referred to as long-term culture-initiating cells (LTC-ICs) because they generate CFCs for at least 5 weeks in long-term cultures containing stromal cell feeder layers. [5][6][7][8] Progenitor cells from patients with MDS display impaired responses to various growth factors in vitro, [9][10][11][12] although growth factor administration in vivo can improve the output of mature blood cells.…”

Section: Introductionmentioning

confidence: 99%

Engraftment of NOD/SCID-β2 microglobulin null mice with multilineage neoplastic cells from patients with myelodysplastic syndrome

Thanopoulou

Cashman

Kakagianne

et al. 2004

Blood

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The development of immunodeficient mouse xenograft models has greatly facilitated the investigation of some human hematopoietic malignancies, but application of this approach to the myelodysplastic syndromes (MDSs) has proven difficult. We now show that cells from most MDS patients (including all subtypes) repopulate nonobese diabetic-severe combined immunodeficient (scid)/scid-␤2 microglobulin null (NOD/SCID-␤2m ؊/؊ ) mice at least transiently and produce abnormal differentiation patterns in this model. Normal marrow transplants initially produce predominantly erythroid cells and later predominantly B-lymphoid cells in these mice, whereas most MDS samples produced predominantly granulopoietic cells. In 4 of 4 MDS cases, the regenerated cells showed the same clonal markers (trisomy 8, n ‫؍‬ 3; and 5q؊, n ‫؍‬ 1) as the original sample and, in one instance, regenerated trisomy 8 ؉ B-lymphoid as well as myeloid cells were identified. Interestingly, the enhanced growth of normal marrow obtained in NOD/SCID-␤2m ؊/؊ mice engineered to produce human interleukin-3, granulocyte-macrophage colony-stimulating factor, and Steel factor was seen only with 1 of 7 MDS samples. These findings support the concept that human MDS originates in a transplantable multilineage hematopoietic stem cell whose genetic alteration may affect patterns of differentiation and responsiveness to hematopoietic growth factors.

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Hematopoietic progenitor cells from patients with myelodysplastic syndromes: in vitro colony growth and long-term proliferation

Cited by 33 publications

References 22 publications

Stage-Specific Human Induced Pluripotent Stem Cells Map the Progression of Myeloid Transformation to Transplantable Leukemia

Stage-Specific Human Induced Pluripotent Stem Cells Map the Progression of Myeloid Transformation to Transplantable Leukemia

Flow cytometry evaluation of erythroid and myeloid dysplasia in patients with myelodysplastic syndrome

Engraftment of NOD/SCID-β2 microglobulin null mice with multilineage neoplastic cells from patients with myelodysplastic syndrome

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