Diamond-Blackfan anemia: heterogenous response of hematopoietic progenitor cells in vitro to the protein product of the steel locus

Olivieri, NF; Grünberger, Thomas; Ben‐David, Yaacov; Ng, Judith; Williams, DE; Lyman, S D; Anderson, D. M.; Axelrad, AA; Correa, Paulo N.; Bernstein, A

doi:10.1182/blood.v78.9.2211.bloodjournal7892211

Cited by 14 publications

(20 citation statements)

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“…In vitro analysis with haemopoietic growth factors has demonstrated varying levels of erythroid response, despite absent erythroid maturation i n vivo (Freedman et al, 1976;Nathan et al, 1978;Halperin et al, 1989;Olivieri et al, 1991b;Abkowitz et al, 1991;Alter et al, 1992). Most work has centred on simple unfractionated marrow mononuclear cells, although the few studies on partially purified populations have c o n k e d the location of the defect in DBA to be in the early erythroid precursors (Tsai et al, 1989;Bagnara et al, 1991).…”

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confidence: 99%

Diamond‐Blackfan anaemia: three patterns of in vitro response to haemopoietic growth factors

1995

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Culture of bone marrow from patients with Diamond-Blackfan anaemia (DBA) has previously shown a variable progenitor response to growth factor stimulation. An extensive standardized study has now been undertaken to investigate the presence of distinct sub-groups in this disorder. In vitro response of bone marrow progenitors to recombinant human growth factors, including stem cell factor, was examined in 18 DBA patients and five normal donors, assessing BFU-E, CFU-GM and CFU-GEMM development. In 16 of the DBA patients a synergistic response to combinations of growth factors was observed with optimal growth in cultures containing erythropoietin, interleukin-3 and stem cell factor. Growth factor induced erythroid response formed three distinct groups, based on BFU-E numbers: type I (mean age 4.87 years) showed > 70% normal erythroid response; type II (mean age 13.87 years) showed < 70% normal; and type III (mean age 15.29 years) < 5% normal. CFU-GM response also followed the trigrouping. The results suggest more than one pathogenic mechanism for the erythroid failure in DBA, indicating DBA may be composed of more than one distinct disorder, and further suggest the defect in DBA may not be confined to the erythroid series.

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confidence: 99%

Diamond‐Blackfan anaemia: three patterns of in vitro response to haemopoietic growth factors

1995

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“…Various reports have shown using in vitro studies that IL-3 ( EPO) increases BFU-E numbers in DBA BMMC Abkowitz et al, 1991;Bagnara et al, 1991;Lipton et al, 1986;Olivieri et al, 1991). Our studies have shown that only a small proportion show reasonable increases in erythroid colonies with addition of SCF being the better option (in vitro) for normalizing colony numbers (McGuckin et al, 1995a).…”

Section: Discussionmentioning

confidence: 51%

In vitro progenitor analysis in a Diamond Blackfan anaemia patient who responded once but not twice to interleukin‐3 therapy, using short‐term and long‐term cultures and c‐kit analysis

et al. 1996

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Interleukin-3 (IL-3) therapy as a treatment for Diamond Blackfan anaemia (DBA) patients has been largely disappointing despite early hope it would be suitable for stimulating arrested erythropoiesis. Initial hope came from in vitro discoveries that IL-3 (+EPO) generated well-haemoglobinized BFU-E colonies in some patients, but was soon tempered by the realization that in vitro and in vivo IL-3 response did not, in the majority of cases, correlate. Nevertheless in vitro testing has been the main focus in analysing the abnormality in the stem and progenitor cell compartment in DBA. Here we report in vitro analysis of a DBA patient who responded once to IL-3 therapy, but not a second time following relapse, using short-term culture, long-term culture and c-kit analysis. Progenitor numbers before and after the first therapy were in the high normal range, but after relapse were much reduced below normal levels. Long-term cultures suggested some arrested progenitors had been reactivated into normal cycle by the first therapy, but may not have been replaced by more immature progenitors. c-kit analysis revealed increased expression in all tested cell populations. These results imply that the first IL-3 therapy reactivated some erythroid progenitors but left the progenitor pool depleted when more immature cells remained arrested.

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“…These results provided further evidence for cellular heterogeneity underlying the pathogenesis of DBA and raised the possibility that there may be more than one underlying molecular basis for the disease. No gross abnormalities in the genetic structure of either the c-kit or Steel loci were identified using Southern analyses, and gene sequencing studies that were subsequently performed did not disclose mutations in c-kit or Steel loci [13,25,261. The seemingly normal response in culture of the progenitor cells from some DBA patients to Steel factor with or without the addition of IL-3 raised the possibility of using this novel growth factor as a therapeutic agent in DBA.…”

Section: Phurmacologic Modularion Of Dba Colony Growthmentioning

confidence: 98%

“…In vitro studies with IL-3 were recently extended to examine the effect of Steel factor, alone and in combination with IL-3, on DBA erythroid colony growth [13,[22][23][24]. Three patterns of in vitro marrow response to IL-3 and/or Steel were observed among 10 DBA patients in the Toronto series: those that responded quantitatively and qualitatively almost as well as cells from normal marrow, those that responded at an intermediate level, and those that did not respond at aII [13].…”

Section: Phurmacologic Modularion Of Dba Colony Growthmentioning

confidence: 99%

Erythropoiesis in diamond-blackfan anemia and the role of interleukin 3 and steel factor

Freedman

1996

STEM CELLS

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Diamond-Blackfan anemia (DBA) is pleiotropic clinically and in vitro, and there is a strong suspicion that DBA is really a family of diseases that shares a common hematological phenotype. Although standard clonogenic assays of erythroid progenitors have been very informative about pathogenesis, they are not diagnostic of DBA, have no relationship to the clinical presentation and do not relate to the hemoglobin level or to the percentage of marrow erythroids at the time of study. Studies on progenitor-enriched marrow cells have furthered our understanding of DBA and have clearly shown marked differences among patients with respect to erythropoietin and "burst-promoting activity" responsiveness. In vitro addition of corticosteroids, interleukin 3 (IL-3) and/or Steel factor has produced a corrective effect on erythropoiesis in some DBA patients and has prompted clinical trials with IL-3 with variable results. It is clear that there is a disparity between the vitro data and clinical outcome, and therefore, the erythroid progenitor responsiveness to steroids and cytokines has limited predictive value clinically. Based on more than two decades of study, a model of DBA has evolved based on putative blocks at various stages along the erythropoietic differentiation pathway. These blocks likely represent a disorder of receptor-ligand interaction involving one or more growth-promoting cytokines.

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Diamond-Blackfan anemia: heterogenous response of hematopoietic progenitor cells in vitro to the protein product of the steel locus

Cited by 14 publications

References 0 publications

Diamond‐Blackfan anaemia: three patterns of in vitro response to haemopoietic growth factors

Diamond‐Blackfan anaemia: three patterns of in vitro response to haemopoietic growth factors

In vitro progenitor analysis in a Diamond Blackfan anaemia patient who responded once but not twice to interleukin‐3 therapy, using short‐term and long‐term cultures and c‐kit analysis

Erythropoiesis in diamond-blackfan anemia and the role of interleukin 3 and steel factor

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