Notch Activation Is an Early and Critical Event during T-Cell Leukemogenesis in Ikaros-Deficient Mice

Dumortier, Alexis; Jeannet, Robin; Kirstetter, Peggy; Kleinmann, Eva; Sellars, MacLean; Santos, Nuno; Thibault, Christelle; Barths, Jochen; Ghysdael, Jacques; Punt, Jennifer A.; Kastner, Philippe; Chan, Susan

doi:10.1128/mcb.26.1.209-220.2006

Cited by 146 publications

(187 citation statements)

References 60 publications

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“…Several target genes have been identified that are differentially regulated by Notch and Ik, including Hes1 and Deltex. Interestingly, these two proteins have been shown to be upregulated not only in thymic lymphomas, but also in premalignant thymocytes of mice expressing low levels of Ik (Dumortier et al, 2006). Increase in Hes1 and Deltex was accompanied by truncating mutations in the PEST domain of Notch in a large percentage of tumors.…”

Section: Ikaros: a Transcriptional Repressor And Inhibitor Of Notch-imentioning

confidence: 99%

It's T-ALL about Notch

2008

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Section: Ikaros: a Transcriptional Repressor And Inhibitor Of Notch-imentioning

confidence: 99%

It's T-ALL about Notch

2008

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“…Furthermore, cooperative mutations causing a reduction in Ikaros activity and an increase in Notch1 activation promote T-cell leukemogenesis. 30,31 To evaluate the activity of Notch signaling in cells carrying alterations in Ikaros and/or Notch1, we measured the Hes1 transcript level in TL and normal thymus mRNAs by real-time RT-PCR. All TLs were classified into four 8 categories: (i) both Ikaros and Notch1 were mutated (IK-mut/ NOTCH-mut); (ii) only Ikaros was mutated (IK-mut); (iii) only Notch1 was mutated (NOTCH-mut) and (iv) neither Ikaros nor Notch1 was mutated (no-mut).…”

Section: Analysis Of Hes1 Transcription As a Measure Of Notch Signalingmentioning

confidence: 99%

Ikaros is a critical target during simultaneous exposure to X‐rays and N‐ethyl‐N‐nitrosourea in mouse T‐cell lymphomagenesis

Hirano

Kakinuma

Amasaki³

et al. 2012

Intl Journal of Cancer

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Cancer risk associated with radiation exposure is considered the result of concurrent exposure to other natural and manmade carcinogens. Available data on the molecular characteristics of cancer after simultaneous exposure to radiation and chemicals are insufficient. In our study, we used a mouse thymic lymphoma (TL) model that was synergistically induced by simultaneous exposure to X-rays and N-ethyl-N-nitrosourea (ENU) at subcarcinogenic doses and analyzed the mutation frequency and spectrum of the TL-associated genes Ikaros, Notch1, p53 and Kras. We found that the point mutation frequency in Ikaros was significantly increased to 47% for simultaneous exposure compared to 13 and 0% for X-ray and ENU exposure alone, respectively. These mutations were mostly G:C > A:T at non-CpG sites and T:A > C:G, both of which are characteristic of ENU mutagenesis. About half of the point mutations were accompanied by loss of heterozygosity (LOH), typical of X-irradiation. The remaining half did not include LOH, which suggests that they were dominant-negative mutations. In Notch1, the frequency of abnormalities was high (>58%) regardless of the treatment, suggesting that Notch1 aberration may be important for T-cell lymphomagenesis. The p53 and Kras mutation frequencies were low for all treatments (<23%). Importantly, the frequency of TLs containing mutations in multiple genes, especially both Ikaros and Notch1, increased after simultaneous exposure. Thus, after simultaneous exposure, Ikaros is a critical target and is inactivated by ENU-induced point mutations and/or X-ray-induced LOH in T-cell lymphomagenesis. Furthermore, concomitant alterations of multiple tumor-associated genes may contribute to enhanced lymphomagenesis after simultaneous exposure.A multitude of natural and manmade chemicals with cancerinitiating and cancer-promoting potential are present in the environment. Many human cancers show considerable dependence on lifestyle, such as the use of tobacco, and dietary factors. 1 Moreover, radiation carcinogenesis in humans is considered to result from the combined effect of radiation exposure and environmental carcinogens. There have been many attempts to estimate the risk of such combined exposure in animal and cell culture models. 2,3 There is, however, almost no information about the molecular mechanism that leads to carcinogenesis following combined exposure. Murine thymic lymphoma (TL) can be reproducibly induced by exposure to ionizing radiation and chemical carcinogens such as N-ethyl-N-nitrosourea (ENU), and this model is considered useful in the search for and Key words: simultaneous exposure, X-ray, N-ethyl-N-nitrosourea, thymic lymphoma, Ikaros Abbreviations: B-ALL: B-cell acute lymphoblastic leukemia; ENU: N-ethyl-N-nitrosourea; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; gpt: guanine phosphoribosyltransferase; HD: heterodimerization; Hes1: hairy enhancer of split-1; LOH: loss of heterozygosity; Mgmt: O 6 -methylguanine-DNA methyltransferase; PEST: polypeptide rich in proline, glutamate, serine and...

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“…Perhaps the answer lies in the coordinated deregulation of Ikaros (diminished activity) and Notch (constitutive activity) pathways that takes place during the process of T cell leukemogenesis, as observed both in mouse and man [18][19][20][21]. Notch signaling is essential for T cell development and regulates T cell proliferation [22][23][24][25].…”

Section: Altered Lymphocyte Populations But No Leukemogenesis In Oldmentioning

confidence: 99%

“…The following antibodies were used: anti-CD4 (GK1.5), anti-CD8 (53-6.7), anti-TCRb (H57-597), anti-CD69 (H1-2F3), anti-CD45R/B220 (RA3-6B2), anti-CD62L (MEL-14), anti-CD44 (IM7), anti-IgD (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26), anti-IgM (II/41), anti-MHC class II (M5/114.15.2), anti-CD138,anti-CD22.2 (Cy34.1, BD Pharmingen), anti-CD21 (7G6, BD Pharmingen) and anti-CD23 (B3B4, BD Pharmingen). All antibodies were purchased from eBioscience unless otherwise stated.…”

Section: Antibodies For Flow Cytometric Analysesmentioning

confidence: 99%

Expression of a non‐DNA‐binding Ikaros isoform exclusively in B cells leads to autoimmunity but not leukemogenesis

et al. 2007

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Ikaros is a transcriptional regulator whose function is essential for B cell development. It is expressed in the hematopoietic stem cell (HSC) through the mature B cell stage. Using genetically engineered mice in which the endogenous Ikaros gene is disrupted, it has been shown that a lack of Ikaros leads to a block in B cell development and that its severe diminution results in a hyperresponsive B cell compartment. Ikaros expression within the HSC has led to speculation as to whether the role of Ikaros in B cell biology is largely accomplished prior to B cell specification. In addition, widespread expression of Ikaros in hematopoietic cells leads to the possibility that some or all of the observed defects are not B cell autonomous. In this report, we demonstrate that over-expression of a dominant interfering Ikaros isoform exclusively in B cells has profound effects on mature B cell function. We provide evidence that continued high-level expression of Ikaros is essential for homeostasis of peripheral lymphocytes and maintenance of B cell tolerance. We also show that deregulation of Ikaros activity does not rapidly result in B cell leukemogenesis as it does with 100% penetrance within the T cell lineage.

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Notch Activation Is an Early and Critical Event during T-Cell Leukemogenesis in Ikaros-Deficient Mice

Abstract: The Ikaros transcription factor is both a key regulator of lymphocyte differentiation and a tumor suppressor in T lymphocytes. Mice carrying a hypomorphic mutation (Ik L/L ) in the Ikaros gene all develop thymic lymphomas. Ik

Cited by 146 publications

References 60 publications

It's T-ALL about Notch

It's T-ALL about Notch

Ikaros is a critical target during simultaneous exposure to X‐rays and N‐ethyl‐N‐nitrosourea in mouse T‐cell lymphomagenesis

Expression of a non‐DNA‐binding Ikaros isoform exclusively in B cells leads to autoimmunity but not leukemogenesis

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