Leukaemia inhibitory factor is necessary for maintenance of haematopoietic stem cells and thymocyte stimulation

Escary, Jean-Louis; Perreau, Jacqueline; Duménil, Dominique; Ezine, Sophie; Brûlet, Philippe

doi:10.1038/363361a0

Cited by 356 publications

(197 citation statements)

References 24 publications

Supporting

Mentioning

188

Contrasting

Unclassified

Order By: Relevance

“…47,48 Using LIF-deficient mice, Escary et al 49 demonstrated that LIF is required to maintain survival of hematopoietic stem cells (but not their terminal differ- entiation) and that thymic T cells require LIF to respond to concanavalin A, an observation possibly linked to the finding that LIF is required to maintain a functional thymic epithelium. 19 For human lymphocytes, release of LIF appears to be specific to T cells and to CD4 þ T cells in particular.…”

Section: Lif In T Cellsmentioning

confidence: 99%

LIF in the regulation of T-cell fate and as a potential therapeutic

Metcalfe

2011

Genes Immun

View full text Add to dashboard Cite

At the heart of lineage commitment within the adaptive immune response is the intrinsic genetic plasticity of the naive peripheral T lymphocyte (T cell). Primary activation by presentation of cognate antigen is coupled to rapid T-cell cycling and progressive epigenetic changes that guide the cell down distinct T-cell lineages, either effector (Th1, Th2, Th17) or tolerogenic (Treg). Fate choice is influenced both by strength of the priming activation signal and by cues from the micro-environment that are integrated with lineage-specific gene expression profiles, eventually becoming hard-wired in the fully differentiated cell. The micro-environmental cues include cytokines, and the discovery that leukaemia inhibitory factor (LIF) and interleukin (IL)-6 counter-regulate development of the Treg and Th17 lineages places LIF within the core regulatory circuitry of T cells. I first summarise current understanding of LIF and the LIF receptor in the context of T cells. Next, the central relevance of the LIF/IL-6 axis in immune-mediated disease is set in the context of (i) a new nano-therapeutic approach for targeted delivery of LIF and (ii) MARCH-7, a novel E3-ligase discovered to have a central mechanistic role in LIF-mediated T-cell biology, functioning as a rheostat-type regulator of endogenous LIF-signalling.

show abstract

Section: Lif In T Cellsmentioning

confidence: 99%

LIF in the regulation of T-cell fate and as a potential therapeutic

Metcalfe

2011

Genes Immun

View full text Add to dashboard Cite

show abstract

“…57,58 Deficiencies in stem cells and committed progenitors resembling the WT1 defect have also been described for mice lacking the thrombopoietin (TPO) receptor c-mpl and for mice lacking the growth factors interleukin-6 (IL-6), kit ligand and Lif, and the HOX cofactor Pbx1. 57,[59][60][61][62] Hematopoietic defects of WT1-deficient mice could be the consequence of the failure of regulation by WT1 of one or more hematopoietic signaling pathways. If receptor expression levels are reduced by the absence of WT1, a hematopoietic phenotype resembling the WT1-negative hematopoietic cell would be expected.…”

Section: Discussionmentioning

confidence: 99%

Role of the WT1 tumor suppressor in murine hematopoiesis

Alberta

Springett

Rayburn

et al. 2003

Blood

View full text Add to dashboard Cite

The WT1 tumor-suppressor gene is expressed by many forms of acute myeloid leukemia. Inhibition of this expression can lead to the differentiation and reduced growth of leukemia cells and cell lines, suggesting that WT1 participates in regulating the proliferation of leukemic cells. However, the role of WT1 in normal hematopoiesis is not well understood. To investigate this question, we have used murine cells in which the WT1 gene has been inactivated by homologous recombination. We have found that cells lacking WT1 show deficits in hematopoietic stem cell function. Embryonic stem cells lacking WT1, although contributing efficiently to other organ systems, make only a minimal contribution to the hematopoietic system in chimeras, indicating that hematopoietic stem cells lacking WT1 compete poorly with healthy stem cells. In addition, fetal liver cells lacking WT1 have an approximately 75% reduction in erythroid blastforming unit (BFU-E), erythroid colonyforming unit (CFU-E), and colony-forming unit-granulocyte macrophage-erythroidmegakaryocyte (CFU-GEMM). However, transplantation of fetal liver hematopoietic cells lacking WT1 will repopulate the hematopoietic system of an irradiated adult recipient in the absence of competition. We conclude that the absence of WT1 in hematopoietic cells leads to functional defects in growth potential that may be of consequence to leukemic cells that have alterations in the expression of WT1. IntroductionWT1 was isolated as a tumor-suppressor gene on the basis of its deletion in a subset of patients with Wilms tumor, a pediatric cancer of the kidney. 1 In addition to its mutation in 5% to 10% of Wilms tumor patients, mutations of WT1 have been implicated in a variety of other cancers including mesotheliomas, desmoplastic round cell tumors, and leukemias. 1 WT1 encodes a protein of 52 to 54 kD, containing 4 zinc fingers of the Cys2 His2 class, that has been demonstrated to act as transcription factor. 1 Potential transcriptional targets for WT1 include a variety of growth factor and growth factor receptor genes. 1 An additional role for WT1 in RNA processing has also been proposed. 1 Many leukemias, including up to 80% of acute myeloid leukemias (AMLs), have been demonstrated to express WT1. [2][3][4][5][6][7][8][9][10] Mutations of WT1 have been found in approximately 5% to 10% of AMLs, similar to the level seen in Wilms tumors, and sporadically in a variety of other leukemias. [11][12][13][14][15][16][17][18] Manipulation of WT1 expression in leukemia cells results in alterations in differentiation and growth potential. [19][20][21][22][23][24][25][26][27][28] In the treatment of leukemia, expression of WT1 in the peripheral blood and bone marrow has been suggested to be an indicator of clinical relapse. Attempts have been made to correlate WT1 expression with progression of disease and prognosis in several types of hematologic malignancies. 3,[29][30][31][32][33][34][35][36][37] The clinical use of anti-WT1 cytotoxic T-lymphocytes (CTLs) for preferential destruction of WT1-expre...

show abstract

“…Mice lacking LIF [28,29] or the LIF receptor (LIFR) do not have an obvious cardiac phenotype [30]. This suggests that LIFR-independent members of this cytokine family are sufficient to support normal cardiac development.…”

Section: Discussionmentioning

confidence: 99%

“…The gp130 cytokine family is characterized by functional redundancy, and the phenotypes of mice lacking individual cytokines [12,17,28,29,45] are much less severe than the phenotypes of mice lacking their shared receptors [10,30,46]. Nonetheless, the early and robust expression of CT-1 in the developing heart tube, and the sustained expression of CT-1 in the adult heart, suggested that CT-1 played a unique role in promoting cardiac myocyte survival and hypertrophy during development and after injury.…”

Section: Discussionmentioning

confidence: 99%

The lack of cardiotrophin-1 alters expression of interleukin-6 and leukemia inhibitory factor mRNA but does not impair cardiac injury response

et al. 2006

View full text Add to dashboard Cite

Cardiotrophin-1 (CT-1) was identified as a growth factor for cardiac myocytes, and CT-1 protects myocytes from cell death. Adult CT-1−/− mice exhibit neural deficits including the loss of preganglionic sympathetic neurons, but their autonomic and cardiac parameters have not been examined. We used these mice to determine if the absence of CT-1 or loss of preganglionic sympathetic input altered heart rate, left ventricular pressure, cardiac contractility (dP/dt), or cell death following ischemia-reperfusion. Basal heart rate was increased in CT-1−/− mice, and this difference was abolished by ganglionic block. Left ventricular pressure and dP/dt were unchanged. Dobutamine stimulated similar increases in heart rate and dP/dt in both genotypes, but ventricular pressure was significantly lower in CT-1 nulls. Cardiac expression of interleukin-6 (IL-6) mRNA was increased significantly in CT-1 null mice, while leukemia inhibitory factor (LIF) mRNA was unchanged. Infarct size normalized to area at risk was no different in CT-1 −/− mice (33.8±1.0 % vs. 37.7±3.2 % WT) 24 hours after ischemia-reperfusion. Induction of IL-6 mRNA after infarct was significantly abrogated in CT-1 null mice compared to wild type mice, but LIF mRNA induction remained significant in CT-1 null mice and might contribute to cardiac protection in the absence of CT-1.

show abstract

Leukaemia inhibitory factor is necessary for maintenance of haematopoietic stem cells and thymocyte stimulation

Cited by 356 publications

References 24 publications

LIF in the regulation of T-cell fate and as a potential therapeutic

LIF in the regulation of T-cell fate and as a potential therapeutic

Role of the WT1 tumor suppressor in murine hematopoiesis

The lack of cardiotrophin-1 alters expression of interleukin-6 and leukemia inhibitory factor mRNA but does not impair cardiac injury response

Contact Info

Product

Resources

About