Trisomy 12 chronic lymphocytic leukemia cells exhibit upregulation of integrin signaling that is modulated by NOTCH1 mutations

Riches, John C.; O’Donovan, Conor J.; Kingdon, Sarah J.; McClanahan, Fabienne; Clear, Andrew; Neuberg, Donna; Werner, Lillian; Croce, Carlo M.; Ramsay, Alan G.; Rassenti, Laura Z.; Kipps, Thomas J.; Gribben, John G.

doi:10.1182/blood-2014-01-552307

Cited by 69 publications

(69 citation statements)

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“…Given the strong link between proliferation and mutagenesis, the greater replication seen in trisomy-12+ B-CLL is consistent with the suggestion that trisomy-12 is a driver mutation which facilitates the accrual of further downstream mutations (33). Heightened growth of trisomy-12+ clones is also in agreement with recent findings that trisomy-12+ B-CLL express elevated CD38 in blood (143). Interestingly, two recent studies found B-CLL with trisomy-12 (or del11q22+) to express elevated levels of insulin growth factor receptor 1 (IGF-1R) (144, 145).…”

Section: Discussionsupporting

confidence: 91%

TLR-9 and IL-15 Synergy Promotes the In Vitro Clonal Expansion of Chronic Lymphocytic Leukemia B Cells

Mongini

Gupta

Boyle

et al. 2015

The Journal of Immunology

109

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Clinical progression of B cell chronic lymphocytic leukemia (B-CLL) reflects the clone’s antigen receptor (BCR) and involves stroma-dependent B-CLL growth within lymphoid tissue. Uniformly elevated expression of Toll-like receptor 9 (TLR-9), occasional MYD88 mutations, and BCR specificity for DNA or antigens physically linked to DNA together suggest that TLR-9 signaling is important in driving B-CLL growth in patients. Nevertheless, reports of apoptosis following B-CLL exposure to CpG oligodeoxynucleotide (ODN) raised questions about a central role for TLR-9. Because normal memory B cells proliferate vigorously to ODN + interleukin-15 (IL-15), a cytokine found in stromal cells of bone marrow, lymph nodes, and spleen, we examined whether this was true for B-CLL cells. Through a CFSE-based assay for quantitatively monitoring in-vitro clonal proliferation/survival, we show that IL-15 precludes TLR-9-induced apoptosis and permits significant B-CLL clonal expansion regardless of the clone’s BCR mutation status. A robust response to ODN+IL-15 was positively linked to presence of chromosomal anomalies (trisomy-12 or ataxia telangiectasia mutated (ATM) anomaly + del13q14), and negatively linked to a very high proportion of CD38+ cells within the blood-derived B-CLL population. Furthermore, a clone’s intrinsic potential for in-vitro growth correlated directly with doubling time in blood, in the case of B-CLL with IGHV-unmutated BCR and <30% CD38+ cells in blood. Finally, in-vitro high-proliferator status was statistically linked to diminished patient survival. The above findings, together with immunohistochemical evidence of apoptotic cells and IL-15-producing cells proximal to B-CLL pseudofollicles in patient spleens, suggest that collaborative ODN and IL-15 signaling may promote in-vivo B-CLL growth.

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Section: Discussionsupporting

confidence: 91%

TLR-9 and IL-15 Synergy Promotes the In Vitro Clonal Expansion of Chronic Lymphocytic Leukemia B Cells

Mongini

Gupta

Boyle

et al. 2015

The Journal of Immunology

109

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“…Tiziana D'Agaro, 1 Michaela Cerri, 2 Annalisa Chiarenza, 3 Kari G. Chaffee, 4 Adalgisa Condoluci, 5 Giovanni D'Arena, 6 Michele Spina, 7 Francesco Zaja, 8 Gabriele Pozzato, 9 Francesco Di Raimondo, 3 Davide Rossi, 5 Giovanni Del Poeta, 10 …”

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“…The peculiar clinical relevance of IGHV mutations in tris12 CLL might be related to a different pathobiology occurring in this subset, mainly involving B cell receptor-related microenvironment-driven pro-survival mechanisms rather than mechanisms ascribed to genetic lesions, 12 such as del13q, typically determining CLL cell survival via upregulation of the BCL2 antiapoptotic protein. Albeit the lack of independent clinical impact of NOTCH1 and SF3B1 mutations need to be confirmed in a prospective series, these findings add to other clinical and phenotypic peculiarities of tris12 CLL, 4,8 thus making a distinction between this CLL subset and the classical CLL.…”

mentioning

confidence: 99%

Mutational status of IGHV is the most reliable prognostic marker in trisomy 12 chronic lymphocytic leukemia

Bulian

Bomben

et al. 2017

Haematologica

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“…The expression of the CD18 variant in patients' B cells is even lower than that of the wild-type form [40]. By contrast, a CLL subgroup of patients harboring trisomy 12 (approximately 16% of CLL patients) show an important increase of LFA-1 and other integrins, associated with high cell proliferation and lymph node infiltration [41] [42]. These data do not clarify the role of LFA-1 in disease progression in CLL and suggest a complex interplay with other adhesion molecules and signaling pathways.…”

Section: Lfa-1 In Chronic Lymphocytic Leukemiamentioning

confidence: 97%

Role of LFA-1 and ICAM-1 in Cancer

Reina

Espel

2017

Preprint

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The lymphocyte function-associated antigen-1 (LFA-1) (also CD11a/CD18 and αLβ2), is just one of many integrins in the human body, but its significance derives from its exclusive presence in leukocytes. In this review, we summarize the studies relating LFA-1 and its major ligand ICAM-1 (CD54) with cancer, through the function of lymphocytes and myeloid cells on tumor cells. We consider how LFA-1 mediates the interaction of leukocytes with tumors and the role of ICAM-1 in tumor dynamics, which can be independent of its interaction with LFA-1. A more detailed examination of LFA's role within B-cell chronic lymphocytic leukemia is made. Finally, we discuss the role of LFA-1-harboring exosomes in tumor growth and metastasis.Keywords: cancer metastasis; chronic lymphocytic leukemia; exosomes; tumor microenvironment LFA-1 is widely expressed in hematopoietic cells, mediating intercellular interactions within the immune system and between leukocytes and non-blood cells. Several intercellular adhesion molecules (ICAM), including ICAM-1 (CD54) are common ligands for LFA-1 [1] [2]. The strength of LFA-1 adhesion varies by adjusting the affinity (conformation), the level of LFA-1 clustering and the force applied by the ligand [3] [4] [5]. LFA-1 can adopt different conformations, from a folded low-affinity inactive one to an open active conformation. The stimulation of cells by receptors like the T-cell receptor or chemokine receptors changes the adhesive properties of LFA-1 in a process called "inside-out" signaling that may open the conformation of LFA-1 and expose its ligand-binding site [6]. In addition, it should be noted that the characteristics of the external ligand binding to LFA-1 initiates a signaling cascade in LFA-1 (named "outside-in" signaling), giving rise to various cellular changes [7]. As with other integrins, LFA-1 is not a mere adhesive contact between cells, but it also mediates signals that modulate the growth, differentiation and survival of the cell. LFA-1 participates in the cytotoxic immune response against tumorsThe T cell cytotoxic response against cancer cells starts when the T cell receptor recognizes a specific tumor antigen on the surface of the cancer cell; this is normally followed by delivery of toxic granules that kill the target cell. In the cytolytic response against virus-infected cells, the adhesion between the cytotoxic lymphocyte and the target cell is not strictly dependent on LFA-1, this however is necessary in the cytolytic response to immunogenic tumors [8] [9]. LFA-1 is an essential initiator of the immunological synapse that forms between the cytotoxic T or NK cell and the cancer cell, and mediates the firm adhesion to the target cell and the polarization of cytotoxic granules towards the target [7] [10] [11]. There is a positive correlation between the maturation state of NK cells, their cytotoxic potential and the activation level of LFA-1 [12].Tumor infiltrating lymphocytes need LFA-1 to adhere to target cells Cancer cells can escape from the immune response by chan...

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Trisomy 12 chronic lymphocytic leukemia cells exhibit upregulation of integrin signaling that is modulated by NOTCH1 mutations

Abstract: Key Points Trisomy 12 CLL cells exhibit upregulated integrin signaling and enhanced VLA-4-directed adhesion and motility. The increased expression of β2-integrins on trisomy 12 CLL cells is modulated by intercurrent NOTCH1 mutations.

Cited by 69 publications

References 31 publications

TLR-9 and IL-15 Synergy Promotes the In Vitro Clonal Expansion of Chronic Lymphocytic Leukemia B Cells

TLR-9 and IL-15 Synergy Promotes the In Vitro Clonal Expansion of Chronic Lymphocytic Leukemia B Cells

Mutational status of IGHV is the most reliable prognostic marker in trisomy 12 chronic lymphocytic leukemia

Role of LFA-1 and ICAM-1 in Cancer

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