ATM activity in T cells is critical for immune surveillance of lymphoma in vivo

Riabinska, Arina; Lehrmann, Daria; Jachimowicz, Ron D.; Knittel, Gero; Fritz, Christian; Schmitt, Anna; Geyer, Aenne; Heneweer, Carola; Wittersheim, Maike; Frenzel, Lukas P.; Torgovnick, Alessandro; Wiederstein, Janica L.; Wunderlich, Claudia M.; Ortmann, Monika; Paillard, Arlette; Wößmann, Wilhelm; Burdach, Stefan; Hansmann, Martin‐Leo; Rosenwald, Andreas; Perner, Sven; Mall, Gita; Klapper, Wolfram; Merseburg, Andrea; Krüger, Marcus; Grüll, Holger; Persigehl, Thorsten; Wunderlich, Frank; Peifer, Martin; Utermöhlen, Olaf; Büttner, Reinhard; Beleggia, Filippo; Reinhardt, Hans Christian

doi:10.1038/s41375-019-0618-2

Cited by 15 publications

(10 citation statements)

References 49 publications

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“…Using a conditionally re-activatable ATM allele, it was possible to reactivate ATM in T cell lymphoma-bearing mice and this led to significant lymphoma shrinkage. Similarly, lymphoma regression in the Eμ-Myc model was observed upon whole organism ATM restoration [86]. All these data indicate a role for ATM loss in driving lymphomas.…”

Section: Ddr and Lymphomasmentioning

confidence: 53%

Targeting the DNA damage response for patients with lymphoma: Preclinical and clinical evidences

Carrassa¹,

Colombo

Damia

et al. 2020

Cancer Treatment Reviews

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The DNA damage response (DDR) is a well-coordinated cellular network activated by DNA damage. The unravelling of the key players in DDR, their specific inactivation in different tumor types and the synthesis of specific chemical inhibitors of DDR represent a new hot topic in cancer therapy. In this article, we will review the importance of DDR in lymphoma development and how this can be exploited therapeutically. Specifically, we will focus on CHK1, WEE1, ATR, DNA-PK and PARP inhibitors, for which preclinical data as single agents or in combination has been accumulating, fostering their clinical development. The few available clinical data on these inhibitors will also be discussed.

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Section: Ddr and Lymphomasmentioning

confidence: 53%

Targeting the DNA damage response for patients with lymphoma: Preclinical and clinical evidences

Carrassa¹,

Colombo

Damia

et al. 2020

Cancer Treatment Reviews

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“…Despite its importance, the mechanism behind DDR alterations and lymphomagenesis remains unclear. Recently, Atm reactivation in initially Atm -deficient B cell lymphomas has been shown to induce tumor regression strongly corroborating the suppressive function of intact DDR on lymphomagenesis [ 43 ]. Thus, addressing the rewired DDR response for B cell lymphoma offers intriguing possibilities for genotype-stratified treatments.…”

Section: Role Of Dna Repair In B Cell Development and Lymphomagenementioning

confidence: 82%

Targeting DNA Repair, Cell Cycle, and Tumor Microenvironment in B Cell Lymphoma

Bröckelmann

Jong

Jachimowicz

2020

Cells

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The DNA double-strand break (DSB) is the most cytotoxic lesion and compromises genome stability. In an attempt to efficiently repair DSBs, cells activate ATM kinase, which orchestrates the DNA damage response (DDR) by activating cell cycle checkpoints and initiating DSB repair pathways. In physiological B cell development, however, programmed DSBs are generated as intermediates for effective immune responses and the maintenance of genomic integrity. Disturbances of these pathways are at the heart of B cell lymphomagenesis. Here, we review the role of DNA repair and cell cycle control on B cell development and lymphomagenesis. In addition, we highlight the intricate relationship between the DDR and the tumor microenvironment (TME). Lastly, we provide a clinical perspective by highlighting treatment possibilities of defective DDR signaling and the TME in mantle cell lymphoma, which serves as a blueprint for B cell lymphomas.

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“…Other DDR kinases such as ATR and ATM have been linked to multiple processes in both the innate and adaptive responses. [27][28][29][30] These functions are largely separate from their roles in NHEJ and HR (homologous recombination) which highlight a clear, yet largely undefined area of immune regulation. The goal of our study was to further understand mechanisms used by DNA-PKcs to govern T cell activation by uncovering novel target proteins.…”

Section: Discussionmentioning

confidence: 99%

DNA-PKcs kinase activity stabilizes the transcription factor Egr1 in activated immune cells

Waldrip

Burdine

Harrison

et al. 2021

Preprint

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DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is known primarily for its function in DNA double-stranded break repair and non-homologous end joining (NHEJ). However, like other DNA damage repair kinases (DDR), DNA-PKcs also has a critical yet undefined role in immunity impacting both myeloid and lymphoid cell lineages spurring interest in targeting DNA-PKcs for therapeutic strategies in immune-related diseases. To gain insight into the function of DNA-PKcs within immune cells, we performed a quantitative phosphoproteomic screen in T cells to identify first order phosphorylation targets of DNA-PKcs. Results indicate that DNA-PKcs phosphorylates the transcription factor Egr1 (early growth response protein 1) at S301. Expression of Egr1 is induced early upon T cell activation and dictates T cell response by modulating expression of cytokines and key costimulatory molecules. Mutation of serine 301 to alanine via CRISPR-Cas9 resulted in increased proteasomal degradation of Egr1 and a decrease in Egr1-dependent transcription of IL2 (interleukin-2) in activated T cells. Our findings identify DNA-PKcs as a critical intermediary link between T cell activation and T cell fate and a novel phosphosite involved in regulating Egr1 activity.

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ATM activity in T cells is critical for immune surveillance of lymphoma in vivo

Cited by 15 publications

References 49 publications

Targeting the DNA damage response for patients with lymphoma: Preclinical and clinical evidences

Targeting the DNA damage response for patients with lymphoma: Preclinical and clinical evidences

Targeting DNA Repair, Cell Cycle, and Tumor Microenvironment in B Cell Lymphoma

DNA-PKcs kinase activity stabilizes the transcription factor Egr1 in activated immune cells

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