A Stromal Inflammasome Ras Safeguard Against Myc-driven Lymphomagenesis

Overview

Journal Nat Immunol

Date 2025 Jan 2

PMID 39747433

Authors

Andrew Kent

Kristel Joy Yee Mon

Zachary Hutchins

Gregory Putzel

Dmitry Zhigarev

Alexander Grier

Baosen Jia

Roderik M Kortlever

Gaetan Barbet

Gerard I Evan

J Magarian Blander

Affiliations

Soon will be listed here.

Abstract

The inflammasome plays multifaceted roles in cancer, but less is known about its function during premalignancy upon initial cell transformation. We report a homeostatic function of the inflammasome in suppressing malignant transformation through Ras inhibition. We identified increased hematopoietic stem cell (HSC) proliferation within the bone marrow of inflammasome-deficient mice. HSCs within an inflammasome-deficient stroma expressed a Ras signature associated with increased Ras pathway- and cancer-related transcripts and heightened levels of cytokine, chemokine and growth factor receptors. Stromal inflammasome deficiency established a poised Ras-dependent mitogenic state within HSCs, which fueled progeny B cell lymphomagenesis upon Myc deregulation in a spontaneous model of B cell lymphoma, and shortened its premalignant stage leading to faster onset of malignancy. Thus, the stromal inflammasome preserves tissue balance by restraining Ras to disrupt the most common oncogenic Myc-Ras cooperation and establish a natural defense against transition to malignancy. These findings should inform preventative therapies against hematological malignancies.

References

Srivastava S, Ghosh S, Kagan J, Mazurchuk R . The Making of a PreCancer Atlas: Promises, Challenges, and Opportunities. Trends Cancer. 2018; 4(8):523-536. DOI: 10.1016/j.trecan.2018.06.007. View

Barnett K, Li S, Liang K, Ting J . A 360° view of the inflammasome: Mechanisms of activation, cell death, and diseases. Cell. 2023; 186(11):2288-2312. PMC: 10228754. DOI: 10.1016/j.cell.2023.04.025. View

Karki R, Kanneganti T . Diverging inflammasome signals in tumorigenesis and potential targeting. Nat Rev Cancer. 2019; 19(4):197-214. PMC: 6953422. DOI: 10.1038/s41568-019-0123-y. View

Kent A, Blander J . Nod-like receptors: key molecular switches in the conundrum of cancer. Front Immunol. 2014; 5:185. PMC: 4005929. DOI: 10.3389/fimmu.2014.00185. View

Basiorka A, McGraw K, Eksioglu E, Chen X, Johnson J, Zhang L . The NLRP3 inflammasome functions as a driver of the myelodysplastic syndrome phenotype. Blood. 2016; 128(25):2960-2975. PMC: 5179338. DOI: 10.1182/blood-2016-07-730556. View

Masters S, Gerlic M, Metcalf D, Preston S, Pellegrini M, ODonnell J . NLRP1 inflammasome activation induces pyroptosis of hematopoietic progenitor cells. Immunity. 2012; 37(6):1009-23. PMC: 4275304. DOI: 10.1016/j.immuni.2012.08.027. View

Zhao X, Zhang C, Hua M, Wang R, Zhong C, Yu J . NLRP3 inflammasome activation plays a carcinogenic role through effector cytokine IL-18 in lymphoma. Oncotarget. 2018; 8(65):108571-108583. PMC: 5752465. DOI: 10.18632/oncotarget.21010. View

Lu F, Zhao Y, Pang Y, Ji M, Sun Y, Wang H . NLRP3 inflammasome upregulates PD-L1 expression and contributes to immune suppression in lymphoma. Cancer Lett. 2020; 497:178-189. DOI: 10.1016/j.canlet.2020.10.024. View

Adams J, Harris A, Pinkert C, Corcoran L, Alexander W, Cory S . The c-myc oncogene driven by immunoglobulin enhancers induces lymphoid malignancy in transgenic mice. Nature. 1985; 318(6046):533-8. DOI: 10.1038/318533a0. View

10.

Harris A, Pinkert C, Crawford M, Langdon W, Brinster R, Adams J . The E mu-myc transgenic mouse. A model for high-incidence spontaneous lymphoma and leukemia of early B cells. J Exp Med. 1988; 167(2):353-71. PMC: 2188841. DOI: 10.1084/jem.167.2.353. View

11.

Kortlever R, Sodir N, Wilson C, Burkhart D, Pellegrinet L, Swigart L . Myc Cooperates with Ras by Programming Inflammation and Immune Suppression. Cell. 2017; 171(6):1301-1315.e14. PMC: 5720393. DOI: 10.1016/j.cell.2017.11.013. View

12.

Land H, Parada L, Weinberg R . Tumorigenic conversion of primary embryo fibroblasts requires at least two cooperating oncogenes. Nature. 1983; 304(5927):596-602. DOI: 10.1038/304596a0. View

13.

Mahauad-Fernandez W, Felsher D . The Myc and Ras Partnership in Cancer: Indistinguishable Alliance or Contextual Relationship?. Cancer Res. 2020; 80(18):3799-3802. PMC: 7501217. DOI: 10.1158/0008-5472.CAN-20-0787. View

14.

Winkler R, Piskor E, Kosan C . Lessons from Using Genetically Engineered Mouse Models of MYC-Induced Lymphoma. Cells. 2023; 12(1). PMC: 9818924. DOI: 10.3390/cells12010037. View

15.

Langdon W, Harris A, Cory S, Adams J . The c-myc oncogene perturbs B lymphocyte development in E-mu-myc transgenic mice. Cell. 1986; 47(1):11-8. DOI: 10.1016/0092-8674(86)90361-2. View

16.

Croxford J, Tang M, Pan M, Huang C, Kamran N, Phua C . ATM-dependent spontaneous regression of early Eμ-myc-induced murine B-cell leukemia depends on natural killer and T cells. Blood. 2013; 121(13):2512-21. PMC: 4260366. DOI: 10.1182/blood-2012-08-449025. View

17.

Cervenak L, Magyar A, Boja R, Laszlo G . Differential expression of GL7 activation antigen on bone marrow B cell subpopulations and peripheral B cells. Immunol Lett. 2001; 78(2):89-96. DOI: 10.1016/s0165-2478(01)00239-5. View

18.

Kumar R, Godavarthy P, Krause D . The bone marrow microenvironment in health and disease at a glance. J Cell Sci. 2018; 131(4). DOI: 10.1242/jcs.201707. View

19.

Spitzer M, Nolan G . Mass Cytometry: Single Cells, Many Features. Cell. 2016; 165(4):780-91. PMC: 4860251. DOI: 10.1016/j.cell.2016.04.019. View

20.

Sidman C, Shaffer D, Jacobsen K, Vargas S, OSMOND D . Cell populations during tumorigenesis in Eu-myc transgenic mice. Leukemia. 1993; 7(6):887-95. View