Evidence from a leukaemia model for maintenance of vascular endothelium by bone-marrow-derived endothelial cells

Gunsilius, Eberhard; Duba, Hans-Christoph; Petzer, Andreas; Kähler, Christian M.; Grünewald, Kurt; Stockhammer, Günther; Gabl, Christoph; Dirnhofer, Stephan; Clausen, Johannes; Gastl, Günther

doi:10.1016/s0140-6736(00)02241-8

Cited by 299 publications

(188 citation statements)

References 16 publications

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“…[73][74][75][76] The presence of MSCs harboring these leukemic fusion genes would explain, at least in part, the higher sensibility of the molecular techniques such as quantitative reverse transcriptase PCR over flow cytometry methods for the detection of minimal residual disease because by flow cytometry we just analyze hematopoietic cells. 77 The detection of the BCR/ABL oncogene and lymphoma-specific genetic aberrations in endothelial cells from chronic myelogenous leukemia and B-cell lymphoma patients suggests that endothelial cells may be part of the neoplastic clone [78][79][80] and that hemangioblasts rather than HSCs appear to be target cells for the first oncogenic hit, which could occur during the first Hilden et al 55 Infant AML 45 F Mauvieux et al 59 Pediatric AML 34 F Adult AML 64 F Wuchter et al 57 Childhood Cellular origin and etiology of the infant pro-B ALL C Bueno et al steps of ESC differentiation and/or in hemangioblasts persisting in adults. 81 The cellular organization and relationships among precursors that initiate embryonic angiogenesis and hematopoiesis in humans have been characterized.…”

Section: Environmental Exposures and Delayed Infection Early In Life mentioning

confidence: 99%

Insights into the cellular origin and etiology of the infant pro-B acute lymphoblastic leukemia with MLL-AF4 rearrangement

et al. 2010

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Infant acute lymphoblastic leukemia (ALL) involving mixedlineage leukemia (MLL) fusions has attracted a huge interest in basic and clinical research because of its prenatal origin, mixed-lineage phenotype, dismal prognosis and extremely short latency. Over 90% of infant ALLs are pro-B ALL harboring the leukemic fusion MLL-AF4. Despite the fact that major achievements have provided a better understanding about the etiology of infant MLL-AF4 þ ALL over the last two decades, key questions remain unanswered. Epidemiological and genetic studies suggest that the in utero origin of MLL rearrangements in infant leukemia may be the result of prenatal exposure to genotoxic compounds. In fact, chronic exposure of human embryonic stem cells (hESCs) to etoposide induces MLL rearrangements and makes hESC more prone to acquire subsequent chromosomal abnormalities than postnatal CD34 þ cells, linking embryonic exposure to topoisomerase II inhibitors to genomic instability and MLL rearrangements. Unfortunately, very little is known about the nature of the target cell for transformation. Neuron-glial antigen 2 expression was initially claimed to be specifically associated with MLL rearrangements and was recently shown to be readily expressed in CD34 þ CD38 þ , but not CD34 þ CD38À cells suggesting that progenitors rather than stem cells may be the target cell for transformation. Importantly, the recent findings showing that MLL-AF4 rearrangement is present and expressed in mesenchymal stem cells from infant patients with MLLAF4 þ ALL challenged our current view of the etiology and cellular origin of this leukemia. It becomes therefore crucial to determine where the leukemia relapses come from and how the tumorstroma relationship is defined at the molecular level. Finally, MLL-AF4 leukemogenesis has been particularly difficult to model and bona fide MLL-AF4 disease models do not exist so far. It is likely that the current disease models are missing some essential ingredients of leukemogenesis in the human embryo/ fetus. We thus propose modeling MLL-AF4 þ infant pro-B ALL using prenatal hESCs.

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Section: Environmental Exposures and Delayed Infection Early In Life mentioning

confidence: 99%

Insights into the cellular origin and etiology of the infant pro-B acute lymphoblastic leukemia with MLL-AF4 rearrangement

et al. 2010

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“…These unexpected results raise the question as to whether hematogenous endothelial cells may also persist in the adult bone marrow. The observation that endothelial cells in chronic myeloid leukemia patients bear the bcr-abl mutation, the hallmark of leukemic cells in this malignancy, may indirectly suggest such affiliation between endothelial cells and hematopoietic cells in the adult (Gunsilius et al 2000). We also have preliminary data indicating that vascular endothelial cells stringently sorted by flow cytometry from the human adult bone marrow can generate, albeit at a very low frequency, hematopoietic cells in culture.…”

Section: Human Embryonic Stem Cells Model the Hemangioblastic Originsmentioning

confidence: 73%

Blood-Forming Endothelium in Human Ontogeny: Lessons From In Utero Development and Embryonic Stem Cell Culture

Zambidis

Oberlin

Tavian

et al. 2006

Trends in Cardiovascular Medicine

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During the early weeks of human gestation, hematopoietic cells first emerge within the extraembryonic yolk sac (primitive hematopoiesis) and secondarily within the truncal arteries of the embryo. This second wave includes the stem cells giving rise to adult-type lymphohematopoiesis. In both yolk sac blood islands and embryonic aorta, hematopoietic cells arise in the immediate vicinity of vascular endothelial cells. In vitro hematopoietic differentiation of endothelial cells stringently sorted from human embryonic and fetal blood-forming tissues has demonstrated that primitive endothelium lies at the origin of incipient hematopoiesis. These anatomically and temporally localized blood-forming endothelial cells are ultimately derived from a rare subset of mesodermal angio-hematopoietic stem cells, or hemangioblasts. The evidence for an early progenitor of blood-forming cells within the walls of human embryonic blood vessels concurs with parallel data obtained from lower vertebrate, avian, and murine models. Importantly, converging results have recently been obtained with in vitro differentiated human embryonic stem cells, in which we have modeled primitive and definitive hematopoiesis via an endothelium-like developmental intermediate.

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“…There is diverse evidence supporting the importance of the BM microenvironment in (135). Nevertheless, the presence of tumor-associated alterations in stroma cells is still controversially discussed.…”

Section: Leukemia Cell Nichementioning

confidence: 99%

Leukemia-associated genetic aberrations in mesenchymal stem cells of children with acute lymphoblastic leukemia

et al. 2010

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Evidence from a leukaemia model for maintenance of vascular endothelium by bone-marrow-derived endothelial cells

Cited by 299 publications

References 16 publications

Insights into the cellular origin and etiology of the infant pro-B acute lymphoblastic leukemia with MLL-AF4 rearrangement

Insights into the cellular origin and etiology of the infant pro-B acute lymphoblastic leukemia with MLL-AF4 rearrangement

Blood-Forming Endothelium in Human Ontogeny: Lessons From In Utero Development and Embryonic Stem Cell Culture

Leukemia-associated genetic aberrations in mesenchymal stem cells of children with acute lymphoblastic leukemia

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