Modulation of B-cell Receptor and Microenvironment Signaling by a Guanine Exchange Factor in B-cell Malignancies

Overview

Journal Cancer Biol Med

Specialty Oncology

Date 2016 Jul 27

PMID 27458535

Citations 3

Authors

Wei Liao

Sanjai Sharma

Affiliations

Soon will be listed here.

Abstract

Objective: Chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) cells over-express a guanine exchange factor (GEF), Rasgrf-1. This GEF increases active Ras as it catalyzes the removal of GDP from Ras so that GTP can bind and activate Ras. This study aims to study the mechanism of action of Rasgrf-1 in B-cell malignancies.

Methods: N-terminus truncated Rasgrf-1 variants have a higher GEF activity as compared to the full-length transcript therefore a MCL cell line with stable over-expression of truncated Rasgrf-1 was established. The B-cell receptor (BCR) and chemokine signaling pathways were compared in the Rasgrf-1 over-expressing and a control transfected cell line.

Results: Cells over-expressing truncated form of Rasgrf-1 have a higher proliferative rate as compared to control transfected cells. BCR was activated by lower concentrations of anti-IgM antibody in Rasgrf-1 over-expressing cells as compared to control cells indicating that these cells are more sensitive to BCR signaling. BCR signaling also phosphorylates Rasgrf-1 that further increases its GEF function and amplifies BCR signaling. This activation of Rasgrf-1 in over-expressing cells resulted in a higher expression of phospho-ERK, AKT, BTK and PKC-alpha as compared to control cells. Besides BCR, Rasgrf-1 over-expressing cells were also more sensitive to microenvironment stimuli as determined by resistance to apoptosis, chemotaxis and ERK pathway activation.

Conclusions: This GEF protein sensitizes B-cells to BCR and chemokine mediated signaling and also upregulates a number of other signaling pathways which promotes growth and survival of these cells.

Citing Articles

The origin of bladder cancer from mucosal field effects.

Bondaruk J, Jaksik R, Wang Z, Cogdell D, Lee S, Chen Y iScience. 2022; 25(7):104551.

PMID: 35747385 PMC: 9209726. DOI: 10.1016/j.isci.2022.104551.

Mutated RAS-associating proteins and ERK activation in relapse/refractory diffuse large B cell lymphoma.

Benoit A, Bou-Petit E, Chou H, Lu M, Guilbert C, Luo V Sci Rep. 2022; 12(1):779.

PMID: 35039569 PMC: 8764096. DOI: 10.1038/s41598-021-04736-0.

The road to ERK activation: Do neurons take alternate routes?.

Miningou N, Blackwell K Cell Signal. 2020; 68:109541.

PMID: 31945453 PMC: 7127974. DOI: 10.1016/j.cellsig.2020.109541.

References

Baouz S, Jacquet E, Bernardi A, Parmeggiani A . The N-terminal moiety of CDC25(Mm), a GDP/GTP exchange factor of Ras proteins, controls the activity of the catalytic domain. Modulation by calmodulin and calpain. J Biol Chem. 1997; 272(10):6671-6. DOI: 10.1074/jbc.272.10.6671. View

Purroy N, Abrisqueta P, Carabia J, Carpio C, Palacio C, Bosch F . Co-culture of primary CLL cells with bone marrow mesenchymal cells, CD40 ligand and CpG ODN promotes proliferation of chemoresistant CLL cells phenotypically comparable to those proliferating in vivo. Oncotarget. 2014; 6(10):7632-43. PMC: 4480705. DOI: 10.18632/oncotarget.2939. View

Stevenson F, Krysov S, Davies A, Steele A, Packham G . B-cell receptor signaling in chronic lymphocytic leukemia. Blood. 2011; 118(16):4313-20. DOI: 10.1182/blood-2011-06-338855. View

Etienne-Manneville S, Hall A . Rho GTPases in cell biology. Nature. 2002; 420(6916):629-35. DOI: 10.1038/nature01148. View

Krysov S, Dias S, Paterson A, Mockridge C, Potter K, Smith K . Surface IgM stimulation induces MEK1/2-dependent MYC expression in chronic lymphocytic leukemia cells. Blood. 2011; 119(1):170-9. DOI: 10.1182/blood-2011-07-370403. View

Ebinu J, Stang S, Teixeira C, Bottorff D, Hooton J, Blumberg P . RasGRP links T-cell receptor signaling to Ras. Blood. 2000; 95(10):3199-203. View

Vigil D, Cherfils J, Rossman K, Der C . Ras superfamily GEFs and GAPs: validated and tractable targets for cancer therapy?. Nat Rev Cancer. 2010; 10(12):842-57. PMC: 3124093. DOI: 10.1038/nrc2960. View

Byrd J, Furman R, Coutre S, Flinn I, Burger J, Blum K . Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013; 369(1):32-42. PMC: 3772525. DOI: 10.1056/NEJMoa1215637. View

Burger J, Gribben J . The microenvironment in chronic lymphocytic leukemia (CLL) and other B cell malignancies: insight into disease biology and new targeted therapies. Semin Cancer Biol. 2013; 24:71-81. DOI: 10.1016/j.semcancer.2013.08.011. View

10.

Burger J, Ghia P, Rosenwald A, Caligaris-Cappio F . The microenvironment in mature B-cell malignancies: a target for new treatment strategies. Blood. 2009; 114(16):3367-75. PMC: 4969052. DOI: 10.1182/blood-2009-06-225326. View

11.

Nakagawa R, Soh J, Michie A . Subversion of protein kinase C alpha signaling in hematopoietic progenitor cells results in the generation of a B-cell chronic lymphocytic leukemia-like population in vivo. Cancer Res. 2006; 66(1):527-34. DOI: 10.1158/0008-5472.CAN-05-0841. View

12.

Buchner M, Fuchs S, Prinz G, Pfeifer D, Bartholome K, Burger M . Spleen tyrosine kinase is overexpressed and represents a potential therapeutic target in chronic lymphocytic leukemia. Cancer Res. 2009; 69(13):5424-32. DOI: 10.1158/0008-5472.CAN-08-4252. View

13.

Burger J, Tsukada N, Burger M, Zvaifler N, DellAquila M, Kipps T . Blood-derived nurse-like cells protect chronic lymphocytic leukemia B cells from spontaneous apoptosis through stromal cell-derived factor-1. Blood. 2000; 96(8):2655-63. View

14.

Burger J, Kipps T . Chemokine receptors and stromal cells in the homing and homeostasis of chronic lymphocytic leukemia B cells. Leuk Lymphoma. 2002; 43(3):461-6. DOI: 10.1080/10428190290011921. View

15.

Mittal A, Chaturvedi N, Rai K, Gilling-Cutucache C, Nordgren T, Moragues M . Chronic lymphocytic leukemia cells in a lymph node microenvironment depict molecular signature associated with an aggressive disease. Mol Med. 2014; 20:290-301. PMC: 4107103. DOI: 10.2119/molmed.2012.00303. View

16.

Zheng Y, Quilliam L . Activation of the Ras superfamily of small GTPases. Workshop on exchange factors. EMBO Rep. 2003; 4(5):463-8. PMC: 1319186. DOI: 10.1038/sj.embor.embor831. View

17.

Bailon E, Ugarte-Berzal E, Amigo-Jimenez I, Van den Steen P, Opdenakker G, Garcia-Marco J . Overexpression of progelatinase B/proMMP-9 affects migration regulatory pathways and impairs chronic lymphocytic leukemia cell homing to bone marrow and spleen. J Leukoc Biol. 2014; 96(2):185-99. DOI: 10.1189/jlb.3HI0913-521R. View

18.

Bos J, Rehmann H, Wittinghofer A . GEFs and GAPs: critical elements in the control of small G proteins. Cell. 2007; 129(5):865-77. DOI: 10.1016/j.cell.2007.05.018. View

19.

Longo P, Laurenti L, Gobessi S, Sica S, Leone G, Efremov D . The Akt/Mcl-1 pathway plays a prominent role in mediating antiapoptotic signals downstream of the B-cell receptor in chronic lymphocytic leukemia B cells. Blood. 2007; 111(2):846-55. DOI: 10.1182/blood-2007-05-089037. View

20.

Rassenti L, Jain S, Keating M, Wierda W, Grever M, Byrd J . Relative value of ZAP-70, CD38, and immunoglobulin mutation status in predicting aggressive disease in chronic lymphocytic leukemia. Blood. 2008; 112(5):1923-30. PMC: 2518894. DOI: 10.1182/blood-2007-05-092882. View