ATM deficiency promotes development of murine B-cell lymphomas that resemble diffuse large B-cell lymphoma in humans

Karen S. Hathcock, Hesed M. Padilla-Nash, Jordi Camps, Dong Mi Shin, Daniel Triner, Arthur L. Shaffer, Robert W. Maul, Seth M. Steinberg, Patricia J. Gearhart, Louis M. Staudt, Herbert C. Morse, Thomas Ried, Richard J. Hodes

Research output: Contribution to journalArticle

Abstract

The serine-threonine kinase ataxia-telangiectasia mutated (ATM) plays a central role in maintaining genomic integrity. In mice, ATM deficiency is exclusively associated with T-cell lymphoma development, whereas B-cell tumors predominate in human ataxia-telangiectasia patients. We demonstrate in this study that when T cells are removed as targets for lymphomagenesis and as mediators of immune surveillance, ATM-deficient mice exclusively develop early-onset immunoglobulin M+ B-cell lymphomas that do not transplant to immunocompetent mice and that histologically and genetically resemble the activated B cell-like (ABC) subset of human diffuse large B-cell lymphoma (DLBCL). These B-cell lymphomas show considerable chromosomal instability and a recurrent genomic amplification of a 4.48-Mb region on chromosome 18 that contains Malt1 and is orthologous to a region similarly amplified in human ABC DLBCL. Of importance, amplification of Malt1 in these lymphomas correlates with their dependence on nuclear factor (NF)-κB, MALT1, and B-cell receptor (BCR) signaling for survival, paralleling human ABC DLBCL. Further, like some human ABC DLBCLs, these mouse B-cell lymphomas also exhibit constitutive BCR-dependent NF-κB activation. This study reveals that ATM protects against development of B-cell lymphomas that model human ABC DLBCL and identifies a potential role for T cells in preventing the emergence of these tumors.

Original languageEnglish (US)
Pages (from-to)2291-2301
Number of pages11
JournalBlood
Volume126
Issue number20
DOIs
StatePublished - Nov 12 2015
Externally publishedYes

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Ataxia Telangiectasia
Lymphoma, Large B-Cell, Diffuse
B-Cell Lymphoma
B-Lymphocytes
Cells
T-cells
B-Lymphocyte Subsets
T-Lymphocytes
Chromosomes, Human, Pair 18
Chromosomal Instability
T-Cell Lymphoma
Protein-Serine-Threonine Kinases
Cytoplasmic and Nuclear Receptors
Amplification
Tumors
Immunoglobulin M
Lymphoma
Neoplasms
Transplants
Chromosomes

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Hathcock, K. S., Padilla-Nash, H. M., Camps, J., Shin, D. M., Triner, D., Shaffer, A. L., ... Hodes, R. J. (2015). ATM deficiency promotes development of murine B-cell lymphomas that resemble diffuse large B-cell lymphoma in humans. Blood, 126(20), 2291-2301. https://doi.org/10.1182/blood-2015-06-654749

ATM deficiency promotes development of murine B-cell lymphomas that resemble diffuse large B-cell lymphoma in humans. / Hathcock, Karen S.; Padilla-Nash, Hesed M.; Camps, Jordi; Shin, Dong Mi; Triner, Daniel; Shaffer, Arthur L.; Maul, Robert W.; Steinberg, Seth M.; Gearhart, Patricia J.; Staudt, Louis M.; Morse, Herbert C.; Ried, Thomas; Hodes, Richard J.

In: Blood, Vol. 126, No. 20, 12.11.2015, p. 2291-2301.

Research output: Contribution to journalArticle

Hathcock, KS, Padilla-Nash, HM, Camps, J, Shin, DM, Triner, D, Shaffer, AL, Maul, RW, Steinberg, SM, Gearhart, PJ, Staudt, LM, Morse, HC, Ried, T & Hodes, RJ 2015, 'ATM deficiency promotes development of murine B-cell lymphomas that resemble diffuse large B-cell lymphoma in humans', Blood, vol. 126, no. 20, pp. 2291-2301. https://doi.org/10.1182/blood-2015-06-654749
Hathcock KS, Padilla-Nash HM, Camps J, Shin DM, Triner D, Shaffer AL et al. ATM deficiency promotes development of murine B-cell lymphomas that resemble diffuse large B-cell lymphoma in humans. Blood. 2015 Nov 12;126(20):2291-2301. https://doi.org/10.1182/blood-2015-06-654749
Hathcock, Karen S. ; Padilla-Nash, Hesed M. ; Camps, Jordi ; Shin, Dong Mi ; Triner, Daniel ; Shaffer, Arthur L. ; Maul, Robert W. ; Steinberg, Seth M. ; Gearhart, Patricia J. ; Staudt, Louis M. ; Morse, Herbert C. ; Ried, Thomas ; Hodes, Richard J. / ATM deficiency promotes development of murine B-cell lymphomas that resemble diffuse large B-cell lymphoma in humans. In: Blood. 2015 ; Vol. 126, No. 20. pp. 2291-2301.
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AU - Padilla-Nash, Hesed M.

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AU - Shin, Dong Mi

AU - Triner, Daniel

AU - Shaffer, Arthur L.

AU - Maul, Robert W.

AU - Steinberg, Seth M.

AU - Gearhart, Patricia J.

AU - Staudt, Louis M.

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AU - Ried, Thomas

AU - Hodes, Richard J.

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