Tcl1 interacts with Atm and enhances NF-κB activation in hematologic malignancies

Eugenio Gaudio; Riccardo Spizzo; Francesco Paduano; Zhenghua Luo; Alexey Efanov; Alexey Palamarchuk; Amanda S. Leber; Mohamed Kaou; Nicola Zanesi; Arianna Bottoni; Stefan Costinean; Laura Z. Rassenti; Tatsuya Nakamura; Thomas J. Kipps; Rami I. Aqeilan; Yuri Pekarsky; Francesco Trapasso; Carlo M. Croce

doi:10.1182/blood-2011-08-374561

Tcl1 interacts with Atm and enhances NF-κB activation in hematologic malignancies

Eugenio Gaudio, Riccardo Spizzo, Francesco Paduano, Zhenghua Luo, Alexey Efanov, Alexey Palamarchuk, Amanda S. Leber, Mohamed Kaou, Nicola Zanesi, Arianna Bottoni, Stefan Costinean, Laura Z. Rassenti, Tatsuya Nakamura, Thomas J. Kipps, Rami I. Aqeilan, Yuri Pekarsky, Francesco Trapasso, Carlo M. Croce^*

^*Corresponding author for this work

Department of Immunology and Cancer Research

Research output: Contribution to journal › Article › peer-review

48 Scopus citations

Abstract

The T-cell leukemia/lymphoma 1 (TCL1) oncogene is a target of chromosomal translocations and inversions at 14q31.2, and its rearrangement in T cells causes T-cell prolymphocytic leukemias. TCL1 dysregulation in B cells is responsible for the development of an aggressive form of chronic lymphocytic leukemia (CLL), the most common human leukemia. We have investigated the mechanisms underlying the oncogenic functions of Tcl1 protein using a mass spectrometry approach and have identified Atm (ataxia-telangiectasia mutated) as a candidate Tcl1-interacting protein. The Tcl1-Atm complex formation was validated by coimmunoprecipitation experiments. Importantly, we show that the association of Atm with Tcl1 leads to enhanced IκBα phosphorylation and ubiquitination and subsequent activation of the NF-κB pathway. Our findings reveal functional cross-talk between Atm and Tcl1 and provide evidence for a novel pathway that could be targeted in leukemias and lymphomas.

Original language	English
Pages (from-to)	180-187
Number of pages	8
Journal	Blood
Volume	119
Issue number	1
DOIs	https://doi.org/10.1182/blood-2011-08-374561
State	Published - 5 Jan 2012

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Gaudio, E., Spizzo, R., Paduano, F., Luo, Z., Efanov, A., Palamarchuk, A., Leber, A. S., Kaou, M., Zanesi, N., Bottoni, A., Costinean, S., Rassenti, L. Z., Nakamura, T., Kipps, T. J., Aqeilan, R. I., Pekarsky, Y., Trapasso, F., & Croce, C. M. (2012). Tcl1 interacts with Atm and enhances NF-κB activation in hematologic malignancies. Blood, 119(1), 180-187. https://doi.org/10.1182/blood-2011-08-374561

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title = "Tcl1 interacts with Atm and enhances NF-κB activation in hematologic malignancies",

abstract = "The T-cell leukemia/lymphoma 1 (TCL1) oncogene is a target of chromosomal translocations and inversions at 14q31.2, and its rearrangement in T cells causes T-cell prolymphocytic leukemias. TCL1 dysregulation in B cells is responsible for the development of an aggressive form of chronic lymphocytic leukemia (CLL), the most common human leukemia. We have investigated the mechanisms underlying the oncogenic functions of Tcl1 protein using a mass spectrometry approach and have identified Atm (ataxia-telangiectasia mutated) as a candidate Tcl1-interacting protein. The Tcl1-Atm complex formation was validated by coimmunoprecipitation experiments. Importantly, we show that the association of Atm with Tcl1 leads to enhanced IκBα phosphorylation and ubiquitination and subsequent activation of the NF-κB pathway. Our findings reveal functional cross-talk between Atm and Tcl1 and provide evidence for a novel pathway that could be targeted in leukemias and lymphomas.",

author = "Eugenio Gaudio and Riccardo Spizzo and Francesco Paduano and Zhenghua Luo and Alexey Efanov and Alexey Palamarchuk and Leber, {Amanda S.} and Mohamed Kaou and Nicola Zanesi and Arianna Bottoni and Stefan Costinean and Rassenti, {Laura Z.} and Tatsuya Nakamura and Kipps, {Thomas J.} and Aqeilan, {Rami I.} and Yuri Pekarsky and Francesco Trapasso and Croce, {Carlo M.}",

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doi = "10.1182/blood-2011-08-374561",

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Gaudio, E, Spizzo, R, Paduano, F, Luo, Z, Efanov, A, Palamarchuk, A, Leber, AS, Kaou, M, Zanesi, N, Bottoni, A, Costinean, S, Rassenti, LZ, Nakamura, T, Kipps, TJ, Aqeilan, RI, Pekarsky, Y, Trapasso, F & Croce, CM 2012, 'Tcl1 interacts with Atm and enhances NF-κB activation in hematologic malignancies', Blood, vol. 119, no. 1, pp. 180-187. https://doi.org/10.1182/blood-2011-08-374561

TY - JOUR

T1 - Tcl1 interacts with Atm and enhances NF-κB activation in hematologic malignancies

AU - Gaudio, Eugenio

AU - Spizzo, Riccardo

AU - Paduano, Francesco

AU - Luo, Zhenghua

AU - Efanov, Alexey

AU - Palamarchuk, Alexey

AU - Leber, Amanda S.

AU - Kaou, Mohamed

AU - Zanesi, Nicola

AU - Bottoni, Arianna

AU - Costinean, Stefan

AU - Rassenti, Laura Z.

AU - Nakamura, Tatsuya

AU - Kipps, Thomas J.

AU - Aqeilan, Rami I.

AU - Pekarsky, Yuri

AU - Trapasso, Francesco

AU - Croce, Carlo M.

PY - 2012/1/5

Y1 - 2012/1/5

N2 - The T-cell leukemia/lymphoma 1 (TCL1) oncogene is a target of chromosomal translocations and inversions at 14q31.2, and its rearrangement in T cells causes T-cell prolymphocytic leukemias. TCL1 dysregulation in B cells is responsible for the development of an aggressive form of chronic lymphocytic leukemia (CLL), the most common human leukemia. We have investigated the mechanisms underlying the oncogenic functions of Tcl1 protein using a mass spectrometry approach and have identified Atm (ataxia-telangiectasia mutated) as a candidate Tcl1-interacting protein. The Tcl1-Atm complex formation was validated by coimmunoprecipitation experiments. Importantly, we show that the association of Atm with Tcl1 leads to enhanced IκBα phosphorylation and ubiquitination and subsequent activation of the NF-κB pathway. Our findings reveal functional cross-talk between Atm and Tcl1 and provide evidence for a novel pathway that could be targeted in leukemias and lymphomas.

AB - The T-cell leukemia/lymphoma 1 (TCL1) oncogene is a target of chromosomal translocations and inversions at 14q31.2, and its rearrangement in T cells causes T-cell prolymphocytic leukemias. TCL1 dysregulation in B cells is responsible for the development of an aggressive form of chronic lymphocytic leukemia (CLL), the most common human leukemia. We have investigated the mechanisms underlying the oncogenic functions of Tcl1 protein using a mass spectrometry approach and have identified Atm (ataxia-telangiectasia mutated) as a candidate Tcl1-interacting protein. The Tcl1-Atm complex formation was validated by coimmunoprecipitation experiments. Importantly, we show that the association of Atm with Tcl1 leads to enhanced IκBα phosphorylation and ubiquitination and subsequent activation of the NF-κB pathway. Our findings reveal functional cross-talk between Atm and Tcl1 and provide evidence for a novel pathway that could be targeted in leukemias and lymphomas.

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Tcl1 interacts with Atm and enhances NF-κB activation in hematologic malignancies

Abstract

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