Cooperation between somatic Ikaros and Notch1 mutations at the inception of T-ALL

Sontani, Yovina; Chapman, Gavin; Papathanasiou, Panagiotis; Dunwoodie, Sally L.; Goodnow, Christopher C.; Hoyne, Gerard F.

doi:10.1016/j.leukres.2011.07.024

Cited by 2 publications

(4 citation statements)

References 43 publications

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Section: Discussionmentioning

confidence: 99%

“…Loss of PTEN has been shown to interfere with normal Ikzf1 splicing [ 42 ], and since IKZF1 and NOTCH1 compete for repression and activation of an overlapping set of genes [ 43 , 44 ], even transient changes in expression of the various functional and dominant-negative IKZF1 isoforms during development (even without mutation) could permit a self-reinforcing Notch signalling state to gain a foothold [ 45 ]. Furthermore, since IKZF1 can bind both the canonical and cryptic internal Notch1 promoter [ 46 ], the important role of Ikzf1 loss/mutation in mouse TL as opposed to human T-ALL (where the importance of its role is contested) [ 47 ] may again be linked to species-specific mechanisms for establishing Notch signalling [ 44 , 48 ]. Notch signalling may remove the selective pressure for Trp53 mutations, by directly blocking TRP53-dependent apoptosis [ 45 , 49 ]; and although increased Notch signalling (in Fbxw7 +/- mice) has been shown to be synergistic with Pten heterozygosity for radiation-induction of TL [ 50 ], as observed in this study, strong Notch signalling from a combined 5′ deletion and PEST mutation may negate the need for Pten inactivation [ 37 ].…”

Section: Discussionmentioning

confidence: 99%

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Genetic Analysis of T Cell Lymphomas in Carbon Ion-Irradiated Mice Reveals Frequent Interstitial Chromosome Deletions: Implications for Second Cancer Induction in Normal Tissues during Carbon Ion Radiotherapy

Blyth¹,

Kakinuma²,

Sunaoshi³

et al. 2015

PLoS ONE

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Monitoring mice exposed to carbon ion radiotherapy provides an indirect method to evaluate the potential for second cancer induction in normal tissues outside the radiotherapy target volume, since such estimates are not yet possible from historical patient data. Here, male and female B6C3F1 mice were given single or fractionated whole-body exposure(s) to a monoenergetic carbon ion radiotherapy beam at the Heavy Ion Medical Accelerator in Chiba, Japan, matching the radiation quality delivered to the normal tissue ahead of the tumour volume (average linear energy transfer = 13 keV.μm-1) during patient radiotherapy protocols. The mice were monitored for the remainder of their lifespan, and a large number of T cell lymphomas that arose in these mice were analysed alongside those arising following an equivalent dose of 137Cs gamma ray-irradiation. Using genome-wide DNA copy number analysis to identify genomic loci involved in radiation-induced lymphomagenesis and subsequent detailed analysis of Notch1, Ikzf1, Pten, Trp53 and Bcl11b genes, we compared the genetic profile of the carbon ion- and gamma ray-induced tumours. The canonical set of genes previously associated with radiation-induced T cell lymphoma was identified in both radiation groups. While the pattern of disruption of the various pathways was somewhat different between the radiation types, most notably Pten mutation frequency and loss of heterozygosity flanking Bcl11b, the most striking finding was the observation of large interstitial deletions at various sites across the genome in carbon ion-induced tumours, which were only seen infrequently in the gamma ray-induced tumours analysed. If such large interstitial chromosomal deletions are a characteristic lesion of carbon ion irradiation, even when using the low linear energy transfer radiation to which normal tissues are exposed in radiotherapy patients, understanding the dose-response and tissue specificity of such DNA damage could prove key to assessing second cancer risk in carbon ion radiotherapy patients.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Genetic Analysis of T Cell Lymphomas in Carbon Ion-Irradiated Mice Reveals Frequent Interstitial Chromosome Deletions: Implications for Second Cancer Induction in Normal Tissues during Carbon Ion Radiotherapy

Blyth¹,

Kakinuma²,

Sunaoshi³

et al. 2015

PLoS ONE

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“…Ikaros inactivation has been proposed to drive oncogenesis of T-ALL at least in part via enhancement of Notch signaling [24][25][26][27][28][29]. However, immunoblotting showed uniformly high levels of cleaved (intracellular) Notch1, as well as the key Notch1 target Hes1, in Lmo2-induced leukemias, regardless of Lmo2-dependence, indicating that Lmo2independence does not result from altered Notch1 signaling (Fig.…”

Section: Loss Of Ikaros Promotes Lmo2-independence In T-all Independently Of Notch Signalingmentioning

confidence: 90%

“…As such, inactivation of Ikaros, and in particular expression of dominant-negative isoforms, leads to rapid induction of T-lymphoblastic leukemia [42,[50][51][52]. How Ikzf1 inactivation causes murine T-ALL remains unclear, but several studies have shown that this can cause amplification of Notch signaling [24][25][26][27][28][29]. In our study, however, both Lmo2-dependent and -independent leukemias showed similar activating mutations in Notch1, and strong expression of intracellular (cleaved) Notch1 and the Notch1 target Hes1.…”

Section: Discussionmentioning

confidence: 99%

T-ALL can evolve to oncogene independence

Abdulla

Shields

et al. 2021

Leukemia

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The majority of cases of T-cell acute lymphoblastic leukemia (T-ALL) contain chromosomal abnormalities that drive overexpression of oncogenic transcription factors. However, whether these initiating oncogenes are required for leukemia maintenance is poorly understood. To address this, we developed a tetracycline-regulated mouse model of T-ALL driven by the oncogenic transcription factor Lmo2. This revealed that whilst thymus-resident pre-Leukemic Stem Cells (pre-LSCs) required continuous Lmo2 expression, the majority of leukemias relapsed despite Lmo2 withdrawal. Relapse was associated with a mature phenotype and frequent mutation or loss of tumor suppressor genes including Ikzf1 (Ikaros), with targeted deletion Ikzf1 being sufficient to transform Lmo2-dependent leukemias to Lmo2-independence. Moreover, we found that the related transcription factor TAL1 was dispensable in several human T-ALL cell lines that contain SIL-TAL1 chromosomal deletions driving its overexpression, indicating that evolution to oncogene independence can also occur in human T-ALL. Together these results indicate an evolution of oncogene addiction in murine and human T-ALL and show that loss of Ikaros is a mechanism that can promote self-renewal of T-ALL lymphoblasts in the absence of an initiating oncogenic transcription factor.

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Cooperation between somatic Ikaros and Notch1 mutations at the inception of T-ALL

Cited by 2 publications

References 43 publications

Genetic Analysis of T Cell Lymphomas in Carbon Ion-Irradiated Mice Reveals Frequent Interstitial Chromosome Deletions: Implications for Second Cancer Induction in Normal Tissues during Carbon Ion Radiotherapy

Genetic Analysis of T Cell Lymphomas in Carbon Ion-Irradiated Mice Reveals Frequent Interstitial Chromosome Deletions: Implications for Second Cancer Induction in Normal Tissues during Carbon Ion Radiotherapy

T-ALL can evolve to oncogene independence

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