scholarly journals β-Catenin stabilization stalls the transition from double-positive to single-positive stage and predisposes thymocytes to malignant transformation

Blood ◽  
2007 ◽  
Vol 109 (12) ◽  
pp. 5463-5472 ◽  
Author(s):  
Zhuyan Guo ◽  
Marei Dose ◽  
Damian Kovalovsky ◽  
Rui Chang ◽  
Jennifer O'Neil ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Lymphoblastic Leukemia ◽  
Thymocyte Development ◽  
Tcr Signaling ◽  
Double Positive ◽  
Notch Receptors ◽  
Single Positive ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Genetic Events ◽  
Notch Activation

AbstractActivation of β-catenin has been causatively linked to the etiology of colon cancer. Conditional stabilization of this molecule in pro-T cells promotes thymocyte development without the requirement for pre-TCR signaling. We show here that activated β-catenin stalls the developmental transition from the double-positive (DP) to the single-positive (SP) thymocyte stage and predisposes DP thymocytes to transformation. β-Catenin–induced thymic lymphomas have a leukemic arrest at the early DP stage. Lymphomagenesis requires Rag activity, which peaks at this developmental stage, as well as additional secondary genetic events. A consistent secondary event is the transcriptional up-regulation of c-Myc, whose activity is required for transformation because its conditional ablation abrogates lymphomagenesis. In contrast, the expression of Notch receptors as well as targets is reduced in DP thymocytes with stabilized β-catenin and remains low in the lymphomas, indicating that Notch activation is not required or selected for in β-catenin–induced lymphomas. Thus, β-catenin activation may provide a mechanism for the induction of T-cell–acute lymphoblastic leukemia (T-ALL) that does not depend on Notch activation.

scholarly journals Disregulated expression of the transcription factor ThPOK during T-cell development leads to high incidence of T-cell lymphomas

2015 ◽  
Vol 112 (25) ◽  
pp. 7773-7778 ◽  
Author(s):  
Hyung-Ok Lee ◽  
Xiao He ◽  
Jayati Mookerjee-Basu ◽  
Dai Zhongping ◽  
Xiang Hua ◽  
...  
Keyword(s):  
Transcription Factor ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
T Cell Development ◽  
Cell Receptor ◽  
Cell Development ◽  
Thymocyte Development ◽  
Tcr Signaling ◽  
Double Positive ◽  
Human T Cell

The transcription factor T-helper-inducing POZ/Krueppel-like factor (ThPOK, encoded by the Zbtb7b gene) plays widespread and critical roles in T-cell development, particularly as the master regulator of CD4 commitment. Here we show that mice expressing a constitutive T-cell–specific ThPOK transgene (ThPOKconst mice) develop thymic lymphomas. These tumors resemble human T-cell acute lymphoblastic leukemia (T-ALL), in that they predominantly exhibit activating Notch1 mutations. Lymphomagenesis is prevented if thymocyte development is arrested at the DN3 stage by recombination-activating gene (RAG) deficiency, but restored by introduction of a T-cell receptor (TCR) transgene or by a single injection of anti-αβTCR antibody into ThPOKconst RAG-deficient mice, which promotes development to the CD4+8+ (DP) stage. Hence, TCR signals and/or traversal of the DN (double negative) > DP (double positive) checkpoint are required for ThPOK-mediated lymphomagenesis. These results demonstrate a novel link between ThPOK, TCR signaling, and lymphomagenesis. Finally, we present evidence that ectopic ThPOK expression gives rise to a preleukemic and self-perpetuating DN4 lymphoma precursor population. Our results collectively define a novel role for ThPOK as an oncogene and precisely map the stage in thymopoiesis susceptible to ThPOK-dependent tumor initiation.

NF-κB activation in premalignant mouse tal-1/scl thymocytes and tumors

Blood ◽  
2003 ◽  
Vol 102 (7) ◽  
pp. 2593-2596 ◽  
Author(s):  
Jennifer O'Neil ◽  
Juan-Jose Ventura ◽  
Nicole Cusson ◽  
Michelle Kelliher
Keyword(s):  
Tumor Growth ◽  
Lymphoblastic Leukemia ◽  
Early Event ◽  
Mutant Form ◽  
Thymocyte Development ◽  
Double Positive ◽  
Necrosis Factor Alpha ◽  
Genetic Event ◽  
Single Positive

Abstract TAL-1/SCL activation is a common genetic event in pediatric T-cell acute lymphoblastic leukemia (T-ALL). Expression of tal-1/scl or a DNA binding mutant of tal-1/scl induces arrest of thymocyte development, resulting in decreases in double-positive and single-positive CD4 thymocytes. Moreover, nuclear p65/p50 heterodimers are detected in premalignant tal-1/scl and mut tal-1/scl thymocytes, suggesting that E2A depletion may induce developmental arrest and stimulate NF-κB activation. Increased NF-κB activity is also observed in tal-1/scl tumors and bcl-2 is overexpressed. To examine the contribution of NF-κB to tal-1/scl tumor growth in vivo, we expressed a mutant form of IκBα in tal-1/scl tumor cells. Although expression of mutant IκBα inhibited the tumor necrosis factor alpha (TNF-α)-induced NF-κB response, it had no effect on tumor growth in mice. These data suggest that NF-κB activation is an early event in tal-1/scl-induced leukemogenesis, associated with arrest of thymocyte development, and does not appear to contribute to tal-1/scl-induced tumor growth. (Blood. 2003;102:2593-2596)

Targeting the Leukemia Initiating Cells in a Mouse T-ALL Model.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3474-3474
Author(s):  
Jessica Tatarek ◽  
Kathleen Cullion ◽  
Michelle Kelliher
Keyword(s):  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Fold Increase ◽  
Thymocyte Development ◽  
Double Positive ◽  
Self Renewal ◽  
Oncogenic Pathways ◽  
Single Positive

Abstract Abstract 3474 Poster Board III-411 T cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy that is largely caused by aberrant activation of the TAL1/SCL, LMO1/2 and NOTCH1 oncogenic pathways. Although most patients respond to cytotoxic therapy, 20-30% relapse and currently we cannot distinguish children likely to relapse from those who will respond to therapy. Evidence is emerging that some malignancies are driven by a rare initiating population that is capable of extensive self-renewal and is resistant to conventional chemotherapy. Although the leukemia-initiating cells (L-ICs) have been well documented in AML and CML, it is unclear whether T-ALL is driven by a rare L-IC and whether relapse reflects an inability to eliminate L-ICs. To determine whether T-ALL is driven by a rare L-IC, we utilized a murine model of T-ALL in which expression of the Tal1 and Lmo2 oncogenes arrests thymocyte development via E47/HEB inhibition and 75% of tumors develop spontaneous gain of function mutations in Notch1. We have shown that treatment with γ-secretase inhibitors (GSIs) to inhibit Notch1 activity induces apoptosis of mouse T-ALL cells in vitro and when administered in vivo extends the survival of leukemic mice. We demonstrate that clonal mouse T-ALL tumors are phenotypically heterogeneous, containing immature CD4- and CD8-negative, double negative (DN) 3 and 4 thymic progenitors and differentiated double positive (DP) and/or single positive (SP) leukemic blasts. Importantly, the DN3 or DN4 progenitors are maintained upon serial transplantation of the tumor into syngeneic recipient mice. Injection of serial dilutions of murine T-ALL cells reveal that the tumors are also functionally heterogeneous; with 1/5000-1/50,000 tumor cells exhibiting leukemia initiating activity. We found the CD44-, CD25+ DN3 progenitors enriched in disease potential, whereas mice injected with DP leukemic blasts failed to develop leukemia. Consistently, our preleukemic studies reveal a 3.5-fold increase in the percentage of Notch1 active, DN3/4 thymic progenitors, raising the possibility that Notch1 drives L-IC growth. Collectively, these studies suggest that activation of the Notch1-c-Myc pathway may confer self-renewal capabilities on committed thymic progenitors. The effects of Notch inhibitors on mouse L-IC survival and activity will be discussed. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Distinct roles for Syk and ZAP-70 during early thymocyte development

2007 ◽  
Vol 204 (7) ◽  
pp. 1703-1715 ◽  
Author(s):  
Emil H. Palacios ◽  
Arthur Weiss
Keyword(s):  
Cell Cycle ◽  
Positive Selection ◽  
Tyrosine Kinases ◽  
Cell Cycle Progression ◽  
Thymocyte Development ◽  
Tcr Signaling ◽  
Double Positive ◽  
Temporal Separation ◽  
Single Positive

The spleen tyrosine kinase (Syk) and ζ-associated protein of 70 kD (ZAP-70) tyrosine kinases are both expressed during early thymocyte development, but their unique thymic functions have remained obscure. No specific role for Syk during β-selection has been established, and no role has been described for ZAP-70 before positive selection. We show that Syk and ZAP-70 provide thymocytes with unique and separable fitness advantages during early development. Syk-deficient, but not ZAP-70–deficient, thymocytes are specifically impaired in initial pre-TCR signaling at the double-negative (DN) 3 β selection stage and show reduced cell-cycle entry. Surprisingly, and despite overlapping expression of both kinases, only ZAP-70 appears to promote sustained pre-TCR/TCR signaling during the DN4, immature single-positive, and double-positive stages of development before thymic selection occurs. ZAP-70 promotes survival and cell-cycle progression of developing thymocytes before positive selection, as also shown by in vivo anti-CD3 treatment of recombinase-activating gene 1–deficient mice. Our results establish a temporal separation of Syk family kinase function during early thymocyte development and a novel role for ZAP-70. We propose that pre-TCR signaling continues during DN4 and later stages, with ZAP-70 dynamically replacing Syk for continued pre-TCR signaling.

Altered thymocyte and T cell development in neonatal mice with hyperoxia-induced lung injury

2018 ◽  
Vol 46 (4) ◽  
pp. 441-449
Author(s):  
Sowmya Angusamy ◽  
Tamer Mansour ◽  
Mohammed Abdulmageed ◽  
Rachel Han ◽  
Brian C. Schutte ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lung Injury ◽  
T Cell Development ◽  
Adaptive Immune System ◽  
Cell Development ◽  
Thymocyte Development ◽  
Double Positive ◽  
Neonatal Mice ◽  
Single Positive

Abstract Background: The adaptive immune system of neonates is relatively underdeveloped. The thymus is an essential organ for adaptive T cell development and might be affected during the natural course of oxygen induced lung injury. The effect of prolonged hyperoxia on the thymus, thymocyte and T cell development, and its proliferation has not been studied extensively. Methods: Neonatal mice were exposed to 85% oxygen (hyperoxia) or room air (normoxia) up to 28 days. Flow cytometry using surface markers were used to assay for thymocyte development and proliferation. Results: Mice exposed to prolonged hyperoxia had evidence of lung injury associated alveolar simplification, a significantly lower mean weight, smaller thymic size, lower mean thymocyte count and higher percentage of apoptotic thymocytes. T cells subpopulation in the thymus showed a significant reduction in the count and proliferation of double positive and double negative T cells. There was a significant reduction in the count and proliferation of single positive CD4+ and CD8+ T cells. Conclusions: Prolonged hyperoxia in neonatal mice adversely affected thymic size, thymocyte count and altered the distribution of T cells sub-populations. These results are consistent with the hypothesis that prolonged hyperoxia causes defective development of T cells in the thymus.

CD7/CD19 Double-Positive T-Cell Acute Lymphoblastic Leukemia

2006 ◽  
Vol 83 (4) ◽  
pp. 324-327
Author(s):  
Shinya Fujisawa ◽  
Fumihiko Tanioka ◽  
Toshihiko Matsuoka ◽  
Takachika Ozawa ◽  
Kensuke Naito ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Double Positive ◽  
Cell Acute Lymphoblastic Leukemia

scholarly journals Pak2 is required for actin cytoskeleton remodeling, TCR signaling, and normal thymocyte development and maturation

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Hyewon Phee ◽  
Byron B Au-Yeung ◽  
Olga Pryshchep ◽  
Kyle Leonard O'Hagan ◽  
Stephanie Grace Fairbairn ◽  
...  
Keyword(s):  
T Cell ◽  
Actin Cytoskeleton ◽  
Molecular Mechanisms ◽  
Thymocyte Development ◽  
Tcr Signaling ◽  
Critical Function ◽  
Cytoskeletal Remodeling ◽  
Single Positive ◽  
Cytoskeleton Remodeling ◽  
P21 Activated Kinase

The molecular mechanisms that govern thymocyte development and maturation are incompletely understood. The P21-activated kinase 2 (Pak2) is an effector for the Rho family GTPases Rac and Cdc42 that regulate actin cytoskeletal remodeling, but its role in the immune system remains poorly understood. In this study, we show that T-cell specific deletion of Pak2 gene in mice resulted in severe T cell lymphopenia accompanied by marked defects in development, maturation, and egress of thymocytes. Pak2 was required for pre-TCR β-selection and positive selection. Surprisingly, Pak2 deficiency in CD4 single positive thymocytes prevented functional maturation and reduced expression of S1P1 and KLF2. Mechanistically, Pak2 is required for actin cytoskeletal remodeling triggered by TCR. Failure to induce proper actin cytoskeletal remodeling impaired PLCγ1 and Erk1/2 signaling in the absence of Pak2, uncovering the critical function of Pak2 as an essential regulator that governs the actin cytoskeleton-dependent signaling to ensure normal thymocyte development and maturation.

Altered lymphoid development in mice deficient for the mAF4 proto-oncogene

Blood ◽  
2000 ◽  
Vol 96 (2) ◽  
pp. 705-710 ◽  
Author(s):  
Patricia Isnard ◽  
Nathalie Coré ◽  
Philippe Naquet ◽  
Malek Djabali
Keyword(s):  
Lymphoblastic Leukemia ◽  
Mutant Mice ◽  
Functional Study ◽  
Heterologous Proteins ◽  
Double Positive ◽  
Acute Leukemias ◽  
Knock Out ◽  
Severe Reduction ◽  
Single Positive

Some chromosomal translocations in acute leukemias involve the fusion of the trithorax-related protein Mll (also called HRX, All1, Htrx,) with a variety of heterologous proteins. In acute lymphoblastic leukemia associated with the t(4;11)(q21;q23) translocation, the4q21 gene that fuses with Mll is AF4. To gain insight into the potential role of AF4 in leukemogenesis and development, this gene was inactivated by homologous recombination in mice. As expected from the tissue distribution of the AF4 transcript, development of both B and T cells is affected in AF4 mutant mice. A severe reduction of the thymic double positive CD4/CD8 (CD4+/CD8+) population was observed; in addition most double- and single-positive cells expressed lower levels of CD4 and CD8 coreceptors. Most importantly, the reconstitution of the double-positive compartment by expansion of the double-negative cell compartment was severely impaired in these mutant mice. In the bone marrow pre-B and mature B-cell numbers are reduced. These results demonstrate that the function of the mAF4 gene is critical for normal lymphocyte development. This raises the possibility that the disruption of the normal AF4 gene or its association with Mll function by translocation may orient the oncogenic process toward the lymphoid lineage. This represents the first functional study using a knock-out strategy on one of the Mll partner genes in translocation-associated leukemias.

scholarly journals Pre–T Cell Receptor (Tcr) and Tcr-Controlled Checkpoints in T Cell Differentiation Are Set by Ikaros

1999 ◽  
Vol 190 (8) ◽  
pp. 1039-1048 ◽  
Author(s):  
Susan Winandy ◽  
Li Wu ◽  
Jin-Hong Wang ◽  
Katia Georgopoulos
Keyword(s):  
Cell Differentiation ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
T Cell Differentiation ◽  
Tcr Signaling ◽  
Double Positive ◽  
Single Positive ◽  
T Cell Malignancies ◽  
Deficient Mice

T cell differentiation relies on pre–T cell receptor (TCR) and TCR signaling events that take place at successive steps of the pathway. Here, we show that two of these T cell differentiation checkpoints are regulated by Ikaros. In the absence of Ikaros, double negative thymocytes can differentiate to the double positive stage without expression of a pre-TCR complex. Subsequent events in T cell development mediated by TCR involving transition from the double positive to the single positive stage are also regulated by Ikaros. Nonetheless, in Ikaros-deficient thymocytes, the requirement of pre-TCR expression for expansion of immature thymocytes as they progress to the double positive stage is still maintained, and the T cell malignancies that invariably arise in the thymus of Ikaros-deficient mice are dependent on either pre-TCR or TCR signaling. We conclude that Ikaros regulates T cell differentiation, selection, and homeostasis by providing signaling thresholds for pre-TCR and TCR.

scholarly journals The transcription factor Gli3 regulates differentiation of fetal CD4–CD8– double-negative thymocytes

Blood ◽  
2005 ◽  
Vol 106 (4) ◽  
pp. 1296-1304 ◽  
Author(s):  
Ariadne L. Hager-Theodorides ◽  
Johannes T. Dessens ◽  
Susan V. Outram ◽  
Tessa Crompton
Keyword(s):  
Transcription Factor ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
T Cell Differentiation ◽  
Double Negative ◽  
Thymocyte Development ◽  
Tcr Signaling ◽  
Double Positive ◽  
Dose Dependent

AbstractGlioblastoma 3 (Gli3) is a transcription factor involved in patterning and oncogenesis. Here, we demonstrate a role for Gli3 in thymocyte development. Gli3 is differentially expressed in fetal CD4–CD8– double-negative (DN) thymocytes and is most highly expressed at the CD44+ CD25– DN (DN1) and CD44–CD25– (DN4) stages of development but was not detected in adult thymocytes. Analysis of null mutants showed that Gli3 is involved at the transitions from DN1 to CD44+ CD25+ DN (DN2) cell and from DN to CD4+CD8+ double-positive (DP) cell. Gli3 is required for differentiation from DN to DP thymocyte, after pre–T-cell receptor (TCR) signaling but is not necessary for pre-TCR–induced proliferation or survival. The effect of Gli3 was dose dependent, suggesting its direct involvement in the transcriptional regulation of genes controlling T-cell differentiation during fetal development.

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