Characterization of an interleukin-7-dependent thymic cell line derived from a p53−/− mouse

Kim, Kyungjae; Khaled, Annette R.; Reynolds, Della; Young, Howard A.; Lee, Chong-Kil; Durum, Scott K.

doi:10.1016/s0022-1759(02)00513-6

Cited by 39 publications

(52 citation statements)

References 44 publications

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“…4,[6][7][8] More recently, we have found that TEL-JAK2 can transform to IL-7 independence an immature thymocyte CD4 Ϫ CD8 Ϫ DN cell line (J.G., unpublished observations, February 2004), which normally depends on IL-7 signaling to survive and proliferate in vitro. 28 Taken together, these data indicate that the constitutive tyrosine kinase activity of TEL-JAK2 during the preleukemic phase of the disease likely perturbs the fine-tuned switch from ␥c to pre-TCR signaling to favor cell proliferation and the accumulation of additional pro-oncogenic mutations.Pre-TCR signaling confers an advantage to TEL-JAK2-induced leukemogenesis, as demonstrated by the delayed leukemia onset in mice lacking an endogenous pre-TCR complex. The pre-TCR cooperative effect likely occurs early during the course of the disease since pT␣ surface expression was only found in a small percentage of the leukemic cells from terminally ill mice (data not shown).…”

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Pre-TCR expression cooperates with TEL-JAK2 to transform immature thymocytes and induce T-cell leukemia

Santos

Rickman

Reyniès

et al. 2006

Blood

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The TEL-JAK2 gene fusion, which has been identified in human leukemia, encodes a chimeric protein endowed with constitutive tyrosine kinase activity. TEL-JAK2 transgenic expression in the mouse lymphoid lineage results in fatal and rapid T-cell leukemia/lymphoma. In the present report we show that T-cell leukemic cells from ESR␣-TEL-JAK2 transgenic mice present an aberrant CD8 ؉ differentiation phenotype, as determined by the expression of stage-specific cell surface markers and lineage-specific genes. TEL-JAK2 transforms immature CD4 ؊ CD8 ؊ double-negative thymocytes, as demonstrated by the development of T-cell leukemia with full penetrance in a Rag2-deficient genetic background. This disease is similar to the bona fide TEL-JAK2 disease as assessed by phenotypic and gene profiling analyses. Pre-TCR signaling synergizes with TEL-JAK2 to transform immature thymocytes and initiate leukemogenesis as shown by (1) the delayed leukemia onset in Rag2-, CD3⑀-and pT␣-deficient mice, (2) the occurrence of recurrent chromosomal alterations in pre-TCR-deficient leukemia, and (3) the correction of delayed leukemia onset in Rag2-deficient TEL-JAK2 mice by an H-Y TCR␣␤ transgene that mimics pre-TCR signaling. Although not affecting leukemia incidence and mouse survival, TCR␣␤ expression was shown to facilitate leukemic cell expansion in secondary lymphoid organs. IntroductionIn the thymus, T cells develop from a common CD4 Ϫ CD8 Ϫ double-negative (DN) progenitor into 2 main lineages, ␣␤ and ␥␦, which are defined by the selection of productive rearrangements in the respective T-cell receptor (TCR) loci (for a review, see Aifantis et al 1 ). In mice, DN thymocytes are divided in 4 categories according to CD25 and CD44 expression: DN1 (CD25 Ϫ CD44 ϩ ), DN2 (CD25 ϩ CD44 ϩ ), DN3 (CD25 ϩ CD44 Ϫ ), and DN4 (CD25 Ϫ CD44 Ϫ ). Rag-mediated rearrangement of the TCR␤ locus at the DN3 stage leads to cell surface expression of a functional TCR␤ chain, which assembles with the surrogate pT␣ chain and CD3-signaling proteins to form the pre-TCR complex. Constitutive survival, proliferation, and differentiation signals emanating from the pre-TCR allow T cells to pass through the ␤-selection checkpoint and mature to the DN4, CD4 Ϫ CD8 ϩ immature single-positive (ISP) and CD4 ϩ CD8 ϩ double-positive (DP) stages. The ␤-selected cells rearrange their TCR␣ locus, and only the minority of cells expressing a functional TCR␣␤ complex at the cell surface will either undergo negative selection and die or undergo positive selection and become mature CD4 or CD8 single-positive (SP) thymocytes.Chromosomal rearrangements or point mutations in oncogenes or tumor suppressor genes occur in hematopoietic stem cells (HSCs), uncommitted and committed lymphoid progenitors, or developing thymocytes, thus leading to T-cell leukemia. Chromosomal translocations involving the juxtaposition of protooncogenes to the promoter and enhancer sequences of TCR loci result in deregulated oncogene expression. Chromosomal translocations can also create fusion genes encoding fu...

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Pre-TCR expression cooperates with TEL-JAK2 to transform immature thymocytes and induce T-cell leukemia

Santos

Rickman

Reyniès

et al. 2006

Blood

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“…The IL-7-dependent thymocyte cell line D1 68 was maintained in RPMI-1640 (Mediatech) supplemented with 10% FBS (Hyclone), 2 mM L-glutamine, 100 IU/mL of penicillin (Mediatech),100 g/mL of streptomycin (Mediatech), 50 M ␤-mercaptoethanol (Invitrogen), and 50 ng/mL murine-recombinant IL-7 (PeproTech). The retroviral package cell line phoenix-Eco 69 was maintained in DMEM (Mediatech), supplemented with 10% FBS (Hyclone) and 100 IU/mL of penicillin (Mediatech), and 100 g/mL of streptomycin (Mediatech).…”

Section: Cell Linesmentioning

confidence: 99%

Development of regulatory T cells requires IL-7Rα stimulation by IL-7 or TSLP

Mazzucchelli

Hixon

Spolski

et al. 2008

Blood

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Interleukin-7 (IL-7), a cytokine produced by stromal cells, is required for thymic development and peripheral homeostasis of most major subsets of T cells. We IntroductionRegulatory T (Treg) cells have a critical suppressive function for maintenance of self-tolerance and prevention of autoimmunity, 1,2 and their deficiency can predispose to gastritis, thyroiditis, diabetes and graft-versus-host disease. Initially, Treg cells were identified as a small percentage, approximately 10% to 15%, of mouse CD4 ϩ T cells that expressed CD25, the ␣ chain of IL-2R. 3,4 Treg cells also are reported to express CD45RB, 5 CD62L, 6 cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), 7-9 glucocorticoidinduced tumor necrosis factor (TNF)-like receptor (GITR), [10][11][12] CD103 (␣E␤7 integrin) 13 and forkhead box transcription factor 3 (Foxp3), an intracellular transcriptional regulator. [14][15][16] In vitro, Treg cells can block proliferative responses of both CD4 ϩ and CD8 ϩ CD25 Ϫ cells by a mechanism that remains to be clearly defined but appears to be based on cell contact and to be independent of cytokine production. [17][18][19][20][21] A very recent paper suggests Tregs suppress target cells by interleukin-2 (IL-2) deprivation and subsequent apoptosis. 22 In vivo, Treg cells suppress activation and expansion of self-reactive T cells that have escaped thymic clonal deletion. 1,3,[23][24][25] In addition to cell contact, the suppressive cytokines IL-10 and transforming growth factor (TGF)␤ have been implicated in vivo as mediators of inhibition. [26][27][28][29][30][31][32] Several studies suggest that CD4 ϩ CD25 ϩ T cells mature in the thymus as a distinct T-cell population. 5,7,10,15,29,33 High-affinity IL-2 receptors are constitutively expressed on Treg cells, and IL-2 has been implicated in the development, maintenance, and function of these cells. 34 It has been reported that IL-2 may be required for peripheral expansion and homeostasis, [35][36][37][38] and IL-2 appears to be required for Treg cell function in the periphery. 17,[39][40][41][42] Mice deficient in IL-2, IL-2R␣, or IL-2R␤ lack regulatory T cells 43,44 and develop severe autoimmune disease. 42,[45][46][47][48][49] IL-7 is a cytokine that is produced by stromal cells in lymphoid tissues and is required for development and homeostasis of most subsets of T cells. [50][51][52] The IL-7 receptor is composed of IL-7R␣ and the common cytokine receptor ␥ chain, ␥ c 53,54 . A related stromal factor, thymic stromal lymphopoietin (TSLP), also shares IL-7R␣ but additionally has a distinctive receptor subunit, TSLPR. 55,56 Naive and memory CD4 ϩ T cells require IL-7 for homeostatic survival. 57,58 In vitro it has been shown that IL-7 can, albeit less well than IL-2 or IL-4, promote the proliferation and suppressor function of CD4 ϩ CD25 ϩ cells stimulated with anti-CD3. 40 The Tr1 cell, another type of suppressor cell that acts by secreting suppressive cytokines, has been shown to respond to IL-7 in vitro. 59 It has recently been reported that Treg cells develop, s...

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“…To verify that IL-7/IL-7Ra signaling withdrawal caused the increases in TIF, we performed IF-FISH analysis using an established IL-7-dependent p53 null thymic cell line D1Bcl2 that was resistant to apoptosis because of constitutive expression of Bcl2. 29,30 IL-7 withdrawal from D1Bcl2 cells resulted in cell cycle arrest within 24 h without apparent induction of apoptosis up to 72 h. 30 However, it greatly enhanced the DNA damage signals Figure 4 Genomic instability in DKO thymic lymphomas is further exemplified by marked chromosomal numerical and structural aberrations. Fresh thymic lymphomas harvested from DKO and p53 null mice were prepared for cytogenetic analyses.…”

Section: Resultsmentioning

confidence: 99%

IL-7Rα deficiency in p53null mice exacerbates thymocyte telomere erosion and lymphomagenesis

Kibe

Zhang

Guo³

et al. 2012

Cell Death Differ

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Interleukin-7 (IL-7) is an essential T-cell survival cytokine. IL-7 receptor (IL-7Ra) deficiency severely impairs T-cell development due to substantial apoptosis. We hypothesized that IL-7Ra null -induced apoptosis is partially contributed by an elevated p53 activity. To investigate the genetic association of IL-7/IL-7Ra signaling with the p53 pathway, we generated IL-7Ra null p53 null (DKO) mice. DKO mice exhibited a marked reduction of apoptosis in developing T cells and an augmented thymic lymphomagenesis with telomere erosions and exacerbated chromosomal anomalies, including chromosome duplications, breaks, and translocations. In particular, Robertsonian translocations, in which telocentric chromosomes fuse at the centromeric region, and a complete loss of telomeres at the fusion site occurred frequently in DKO thymic lymphomas. Cellular and molecular investigations revealed that IL-7/IL-7Ra signaling withdrawal diminished the protein synthesis of protection of telomere 1 (POT1), a subunit of telomere protective complex shelterin, leading to telomere erosion and the activation of the p53 pathway. Blockade of IL-7/IL-7Ra signaling in IL-7-dependent p53 null cells reduced POT1 expression and caused telomere and chromosome abnormalities similar to those observed in DKO lymphomas. This study underscores a novel function of IL-7/IL-7Ra during T-cell development in regulating telomere integrity via POT1 expression and provides new insights into cytokinemediated survival signals and T-cell lymphomagenesis. Interleukin-7 (IL-7) is an essential and nonredundant cytokine for T-cell development. 1 Humans and mice deficient in IL-7 receptor (IL-7Ra) incur severe T-cell development defects, manifesting SCID. [1][2][3][4] Early studies have shown that unbalanced survival signals of the Bcl-2 family members contribute to the impaired thymopoiesis in IL-7Ra deficiency. 1 Nevertheless, ectopic expression of Bcl-2 or inactivation of Bcl-2-associated X protein in IL-7Ra null mice only partially rescues the thymopoietic defect, 5-7 suggesting the possible involvement of the other pathways.The tumor-suppressor p53 is a crucial transcription factor in controlling the cell cycle and apoptosis of cells under genotoxic stresses. 8 Early studies show that p53 participates in critical thymopoiesis checkpoints related to T-cell receptor rearrangement and DNA damage repair. 9-11 Emerging evidence suggests that p53 is a crucial regulatory factor of normal physiological processes, such as maintenance of stem cell state, development, tissue homeostasis, and autoimmunity. [12][13][14][15] We hypothesized that p53 activation also contributes to the apoptosis and impaired thymopoiesis in IL-7Ra deficiency. However, the interplay between the IL-7/IL-7Ra signaling and the p53 pathway has not been demonstrated.To decipher the potential genetic association of the IL-7Ra signaling with the p53 pathway, we crossed IL-7Ra null mice with p53 null mice. Intriguingly, genetic deletion of p53 in IL-7Ra null background (IL-7Ra null p53 null , DKO mice) n...

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Characterization of an interleukin-7-dependent thymic cell line derived from a p53−/− mouse

Cited by 39 publications

References 44 publications

Pre-TCR expression cooperates with TEL-JAK2 to transform immature thymocytes and induce T-cell leukemia

Pre-TCR expression cooperates with TEL-JAK2 to transform immature thymocytes and induce T-cell leukemia

Development of regulatory T cells requires IL-7Rα stimulation by IL-7 or TSLP

IL-7Rα deficiency in p53null mice exacerbates thymocyte telomere erosion and lymphomagenesis

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