Lenalidomide reduces survival of chronic lymphocytic leukemia cells in primary cocultures by altering the myeloid microenvironment

Schulz, Angela; Dürr, Claudia; Zenz, Thorsten; Döhner, Hartmut; Stilgenbauer, Stephan; Lichter, Peter; Seiffert, Martina

doi:10.1182/blood-2012-08-447664

Cited by 42 publications

(31 citation statements)

References 39 publications

(58 reference statements)

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“…18,28 We confirmed that lenalidomide reduced CLL survival in contact with NLCs from 54.2% to 44.5% after ten days (n=5; P<0.05) (Online Supplementary Figure S1), as reported by Schulz et al 17 The next part of the study was dedicated to the analysis of the effect of lenalidomide treatment on NLCs. First, we cultured PBMCs from 9 CLL patients for ten days with 0.5 mM or 1 mM lenalidomide or vehicle.…”

Section: Lenalidomide Induces Activation and Proliferation Of Nlcssupporting

confidence: 52%

“…26 The capability of lenalidomide to restrain monocyte migration is in line with studies demonstrating that this drug also interferes with CLL cell chemotaxis, suggesting that CORO1B upregulation and RhoH downregulation may be involved in migration impairment induced by lenalidomide in CLL cells and monocytes. 17,26 Conversely, high levels of RhoH in the presence of chemokine signals impair T-cell chemotaxis, explaining the opposite promoting effect of lenalidomide on T-cell migration. In treated CLL patients, lenalidomide would be expected to restrain monocyte migration towards chemokine gradients generated by CLL-infiltrated cells.…”

Section: Discussionmentioning

confidence: 99%

“…Lenalidomide was reported to modulate the expression of the Rho GTPase RhoH, and the actin binding protein CORO1B in T lymphocytes and CLL cells. 17,26,27 We monitored the expression levels of RhoH and CORO1B mRNA in CLL monocytes (n=6) treated for 4 h with lenalidomide 0.5 mM. Lenalidomide increased the expression levels of CORO1B, whereas it down-modulated RhoH in monocytes (P<0.05) ( Figure 3C and D).…”

Section: Lenalidomide Improves Adhesion and Impairs Migration Of Cll mentioning

confidence: 99%

“…[14][15][16] Recently, lenalidomide was also shown to interfere with the mutualistic interaction between CLL and NLCs. 17 Together these findings prompted us to investigate the functional effects of lenalidomide on NLCs in CLL. We found that lenalidomide modifies CLL-circulating monocytes, inducing firm adhesion to endothelium and loss of migration through modulation of small GTPases.…”

Section: Introductionmentioning

confidence: 99%

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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: Lenalidomide Induces Activation and Proliferation Of Nlcssupporting

confidence: 52%

Section: Discussionmentioning

confidence: 99%

Section: Lenalidomide Improves Adhesion and Impairs Migration Of Cll mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2014

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“…Morande et al (5) recently showed that NLCs were susceptible to Aplidin-induced death, suggesting that its anti-tumoral effects were from targeting CLL cells and NLCs simultaneously . Schulz et al (6) showed that treatment with lenalidomide changed the functional and phenotypic nature of NLCs by interfering with their nurturing properties.…”

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confidence: 99%

Reprogramming Nurse-like Cells with Interferon γ to Interrupt Chronic Lymphocytic Leukemia Cell Survival

Gautam

Fatehchand

Elavazhagan

et al. 2016

Journal of Biological Chemistry

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Nurse like cells (NLCs) 3 are tumor-nurturing cells derived from CD14 ϩ monocytes in chronic lymphocytic leukemia (CLL) patients. In vitro studies have classified NLCs as CLLspecific, tumor-associated macrophage-like cells functioning as immune regulators and also possible inducers of emerging drug resistance (1-3). It has been shown recently that, in patients with diffuse large B cell lymphoma, a high density of CD68 ϩ /CD163 ϩ tumor-associated macrophages was significantly correlated with unfavorable prognosis and poor clinical outcome (4). Interferons have been widely accepted as modulators of macrophage plasticity and activation, and it is known that IFN␥ is capable of promoting the differentiation of monocytic cells (7). With regard to therapeutic use, Miller et al. (8) have shown that IFN␥ is beneficial for treating immune disorders such as systemic sclerosis and that it displays antitumor and antiangiogenic effects both in vitro and in vivo . IFN␥ treatment has also been shown to induce antineoplastic immune responses by sensitizing tumor cells to apoptosis via up-regulation of both MHC class I and II molecules and by enhancing antitumor immune activity while decreasing M2 characteristics in immune cells (9, 10). IFN␥ has been successfully used in cases of ovarian cancer, multiple myeloma (11), and bladder carcinoma and, recently, in malignant gliomas (12).Here we examined the effects of IFN␥ on the phenotype and function of NLCs. We found that IFN␥ significantly increased the expression of the M1-related markers CD86 and HLA-DR as well as the phagocytic receptor Fc␥RI. Concurrently, the prosurvival ligand CD31 was down-regulated. Consistent with this, IFN␥-treated NLCs showed superior phagocytic ability toward both opsonized sheep RBCs (SRBCs) and rituximab-coated CLL cells as well as withdrawal of support for CLL cell survival. These results show that IFN␥ can reprogram NLCs to function as immune effectors and suggest that therapies that enhance IFN␥ production locally may be valuable treatments for CLL, particularly when combined with monoclonal antibodies such as rituximab. Experimental ProceduresPatient Samples-Peripheral blood was collected from CLL patients with informed consent in accordance with the Declaration of Helsinki and under approval from the Institutional Review Board of Ohio State University.NLC Culture-Peripheral blood mononuclear cells were isolated from CLL patient blood by density gradient centrifugation over Ficoll-Hypaque (Nycomed, Oslo, Norway) and resus-

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Rola monocytów w patogenezie przewlekłej białaczki limfocytowej

Łapuć

Eljaszewicz

Kłoczko

et al. 2014

Acta Haematologica Polonica

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Lenalidomide reduces survival of chronic lymphocytic leukemia cells in primary cocultures by altering the myeloid microenvironment

Abstract: Key Points Lenalidomide treatment of primary CLL/nurse-like cell cocultures resulted in significantly decreased viability of CLL cells. Lenalidomide increased IL-10 levels, activation of STAT1, expression of ICAM-1, and migration-related genes, and reduced CLL cell motility.

Cited by 42 publications

References 39 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

Reprogramming Nurse-like Cells with Interferon γ to Interrupt Chronic Lymphocytic Leukemia Cell Survival

Rola monocytów w patogenezie przewlekłej białaczki limfocytowej

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