Identification of outcome-correlated cytokine clusters in chronic lymphocytic leukemia

Yan, Xinfeng; Dozmorov, Igor; Li, Wentian; Yancopoulos, Sophia; Sison, Cristina; Centola, Michael; Jain, Preetesh; Allen, Sheila; Kolitz, Jonathan E.; Kanti, R.; Chiorazzi, Nicholas; Sherry, Barbara

doi:10.1182/blood-2011-03-342436

Cited by 106 publications

(117 citation statements)

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“…On the other hand, there is some evidence to show that an inflammatory microenvironment is induced in survival-supporting culture of CLL cells and that the levels of some inflammatory cytokines are increased in sera of CLL patients compared to healthy controls. 42,50 However, CLL patients with good outcome are characterized by higher levels of several pro-inflammatory cytokines (IL-2, IL-4, IL-15, IL-1β, IL-6, TNFa) as compared to CLL with poor outcome. This implies that a more aggressive disease is accompanied by a progressive suppression of immune cell activation and anti-tumor responses.…”

Section: Discussionmentioning

confidence: 99%

Lenalidomide interferes with tumor-promoting properties of nurse-like cells in chronic lymphocytic leukemia

et al. 2014

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Patients and samplesWritten informed consent was obtained in accordance with the Declaration of Helsinki with a protocol approved by the local Institutional Review Board. CD14 + monocytes were obtained by immunomagnetic selection. To generate NLCs, PBMCs from CLL patients were cultured (10 7 /mL) as previously described. 18Lenalidomide was used at the clinically relevant doses of 0.5 mM, 1 mM and 10 mM as in previous studies.

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Section: Discussionmentioning

confidence: 99%

Lenalidomide interferes with tumor-promoting properties of nurse-like cells in chronic lymphocytic leukemia

et al. 2014

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“…Hence, inhibition of SYK alone is likely to affect multiple disease-relevant survival mechanisms in vivo. In addition, serum levels of several cytokines are increased in CLL (Mahadevan et al, 2009) and have predictive value in disease outcome (Fayad et al, 2001;Lai et al, 2002;Yan et al, 2011). IL-2, IL-4, and alpha interferon promote CLL survival in vitro, reportedly by inducing the upregulation of B-cell lymphoma 2 family proteins (Dancescu et al, 1992;Panayiotidis et al, 1993;Jewell et al, 1994;Castejon et al, 1999).…”

Section: Efficacy Of Prt062070 In Models Of Autoimmunity and Cancermentioning

confidence: 99%

The Novel Kinase Inhibitor PRT062070 (Cerdulatinib) Demonstrates Efficacy in Models of Autoimmunity and B-Cell Cancer

Coffey

Betz

DeGuzman

et al. 2014

J Pharmacol Exp Ther

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The heterogeneity and severity of certain autoimmune diseases and B-cell malignancies warrant simultaneous targeting of multiple disease-relevant signaling pathways. Dual inhibition of spleen tyrosine kinase (SYK) and Janus kinase (JAK) represents such a strategy and may elicit several benefits relative to selective kinase inhibition, such as gaining control over a broader array of disease etiologies, reducing probability of selection for bypass disease mechanisms, and the potential that an overall lower level suppression of individual targets may be sufficient to modulate disease activity. To this end, we provide data on the discovery and preclinical development of PRT062070 [4-(cyclopropylamino)-2-({4-[4-(ethylsulfonyl)piperazin-1-yl]phenyl}amino)pyrimidine-5-carboxamide hydrochloride], an orally active kinase inhibitor that demonstrates activity against SYK and JAK. Cellular assays demonstrated specific inhibitory activity against signaling pathways that use SYK and JAK1/ 3. Limited inhibition of JAK2 was observed, and PRT062070 did not inhibit phorbol 12-myristate 13-acetate-mediated signaling or activation in B and T cells nor T-cell antigen receptor-mediated signaling in T cells, providing evidence for selectivity of action. Potent antitumor activity was observed in a subset of B-cell lymphoma cell lines. After oral dosing, PRT062070 suppressed inflammation and autoantibody generation in a rat collageninduced arthritis model and blocked B-cell activation and splenomegaly in a mouse model of chronic B-cell antigen receptor stimulation. PRT062070 is currently under evaluation in a phase I dose escalation study in patients with B-cell leukemia and lymphoma (NCT01994382), with proof-of-concept studies in humans planned to assess therapeutic potential in autoimmune and malignant diseases.

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“…60 MIG/CXCL9 level is higher in CLL patient sera and is associated with CD38 expression. 61 In addition, a high level of the cytokine cluster CL1, including MIG/CXCL9, is correlated with shorter overall survival, 61 suggesting that a high level of MIG/CXCL9 might predict a poor prognosis in CLL. The expression of MIG/CXCL9 receptor CXCR3 in CLL and splenic marginal zone lymphoma is higher compared with normal circulating B cells and mediates chemotaxis to support CLL survival and migration.…”

mentioning

confidence: 99%

BRAFV600E accelerates disease progression and enhances immune suppression in a mouse model of B-cell leukemia

Tsai

Lakshmanan

Lehman³

et al. 2017

Blood Advances

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Identification of outcome-correlated cytokine clusters in chronic lymphocytic leukemia

Cited by 106 publications

References 50 publications

Lenalidomide interferes with tumor-promoting properties of nurse-like cells in chronic lymphocytic leukemia

Lenalidomide interferes with tumor-promoting properties of nurse-like cells in chronic lymphocytic leukemia

The Novel Kinase Inhibitor PRT062070 (Cerdulatinib) Demonstrates Efficacy in Models of Autoimmunity and B-Cell Cancer

BRAFV600E accelerates disease progression and enhances immune suppression in a mouse model of B-cell leukemia

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