Role of the microenvironment in mantle cell lymphoma: IL-6 is an important survival factor for the tumor cells

Zhang, Liang; Yang, Jing; Qian, Jianfei; Li, Haiyan; Romaguera, Jorge; Kwak, Larry W.; Wang, Michael; Yi, Qing

doi:10.1182/blood-2012-04-424630

Cited by 100 publications

(78 citation statements)

References 37 publications

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“…In that sense, we found mutations of TLR2 in two SOX11-negative/ IGHV-mutated MCL, and these mutations were associated with increased production of IL-1RA and IL-6 by the tumor cells. Notably, high levels of IL-1RA have been associated with aggressive behavior in some lymphomas (35), and IL-6 sustains growth and survival of MCL cells (36). These findings suggest that TLR2 mutations may contribute to the pathogenesis of a subset of SOX11-negative/IGHV-mutated MCL by modulating tumor microenvironment responses.…”

Section: Discussionmentioning

confidence: 84%

Landscape of somatic mutations and clonal evolution in mantle cell lymphoma

Beà

Valdés-Mas

Navarro

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

461

361

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Mantle cell lymphoma (MCL) is an aggressive tumor, but a subset of patients may follow an indolent clinical course. To understand the mechanisms underlying this biological heterogeneity, we performed whole-genome and/or whole-exome sequencing on 29 MCL cases and their respective matched normal DNA, as well as 6 MCL cell lines. Recurrently mutated genes were investigated by targeted sequencing in an independent cohort of 172 MCL patients. We identified 25 significantly mutated genes, including known drivers such as ataxia-telangectasia mutated (ATM), cyclin D1 (CCND1), and the tumor suppressor TP53; mutated genes encoding the anti-apoptotic protein BIRC3 and Toll-like receptor 2 (TLR2); and the chromatin modifiers WHSC1, MLL2, and MEF2B. We also found NOTCH2 mutations as an alternative phenomenon to NOTCH1 mutations in aggressive tumors with a dismal prognosis. Analysis of two simultaneous or subsequent MCL samples by whole-genome/whole-exome (n = 8) or targeted (n = 19) sequencing revealed subclonal heterogeneity at diagnosis in samples from different topographic sites and modulation of the initial mutational profile at the progression of the disease. Some mutations were predominantly clonal or subclonal, indicating an early or late event in tumor evolution, respectively. Our study identifies molecular mechanisms contributing to MCL pathogenesis and offers potential targets for therapeutic intervention.next-generation sequencing | cancer genetics | cancer heterogeneity M antle cell lymphoma (MCL) is a mature B-cell neoplasm characterized by the t(11;14)(q13;q32) translocation leading to the overexpression of cyclin D1 (1). CCND1 is a weak oncogene that requires the cooperation of other oncogenic events to transform lymphoid cells (2). Molecular studies have identified alterations in components of the cell-cycle regulation, DNA damage response, and cell survival pathways (3, 4), but the profile of mutated genes contributing to the pathogenesis of MCL and cooperating with CCND1 is not well defined (1). Most MCL cases have a rapid evolution and an aggressive behavior with an unfavorable outcome with current therapies (5). Paradoxically, a subset of patients follows an indolent clinical evolution with stable disease even in the absence of chemotherapy (6, 7). This favorable behavior has been associated with IGHV-mutated (8, 9) and lack of expression of SOX11 (10, 11), a transcription factor highly specific of MCL that contributes to the aggressive behavior of this tumor (12). However, the molecular mechanisms responsible for this clinical heterogeneity are not well understood.To gain insight into the molecular pathogenesis of MCL we performed whole-genome sequencing (WGS) and whole-exome sequencing (WES) of 29 MCL and further investigated mutated genes in an expanded series of patients. We also analyzed the subclonal heterogeneity of the tumors and their modulation during the evolution of the disease. Results Landscape of Mutations in MCL.We performed WGS and WES of 4 and 29 MCL, respectively. These patients were re...

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Section: Discussionmentioning

confidence: 84%

Landscape of somatic mutations and clonal evolution in mantle cell lymphoma

Beà

Valdés-Mas

Navarro

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

461

361

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“…Recently, the tumor microenvironment was reported to be a source of IL-6 in certain types of malignancy. 20,21 Some researchers have even speculated that the tumor microenvironment may supply IL-6 in SOC. 22 Therefore, hypothetically, there are 2 possible pathways for IL-6 interaction in ovarian cancer: (i) direct pathway via autocrine IL-6 signaling and (ii) IL-6-mediated indirect pathway via paraneoplastic thrombocytosis.…”

Section: Discussionmentioning

confidence: 99%

Venous thromboembolism, interleukin-6 and survival outcomes in patients with advanced ovarian clear cell carcinoma

Matsuo¹,

Hasegawa²,

Yoshino³

et al. 2015

European Journal of Cancer

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“…IL6 is a biologic marker in other lymphoid malignancies, including Hodgkin disease, mantle-cell lymphoma, cutaneous CD30-positive lymphomas, and KSHV-associated malignancies (48)(49)(50)(51)(52). Polymorphisms of different cytokine genes, and particularly of IL6 gene (IL6-174GG genotype) are associated with treatment failure in Hodgkin disease (53).…”

Section: Multiple Myelomamentioning

confidence: 99%

Interleukin-6 as a Therapeutic Target

Rossi

Liu²,

Jourdan

et al. 2015

Clinical Cancer Research

312

277

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Human IL6 is a cytokine produced by many cell types that has pleiotropic effects. In agreement, anti-IL6 therapy reduces inflammation, hepatic acute phase proteins, and anemia and has antiangiogenic effects. Blocking IL6 has demonstrated therapeutic efficacy with drug registration in Castleman disease and inflammatory diseases (rheumatoid arthritis) without major toxicity. Interestingly, the inhibition of C-reactive protein (CRP) production is a trustworthy surrogate marker of anti-IL6 therapy efficacy. Clinically registered IL6 inhibitors include siltuximab, an anti-IL6 mAb, and tocilizumab, an anti-IL6R mAb. In various cancers, in particular plasma cell cancers, large randomized trials showed no efficacy of IL6 inhibitors, despite a full inhibition of CRP production in treated patients in vivo, the numerous data showing an involvement of IL6 in these diseases, and initial short-term treatments demonstrating a dramatic inhibition of cancer cell proliferation in vivo. A likely explanation is the plasticity of cancer cells, with the presence of various subclones, making the outgrowth of cancer subclones possible using growth factors other than IL6. In addition, current therapeutic strategies used in these cancers already target IL6 activity. Thus, anti-IL6 therapeutics are able to neutralize IL6 production in vivo and are safe and useful in inflammatory diseases and Castleman disease.

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Role of the microenvironment in mantle cell lymphoma: IL-6 is an important survival factor for the tumor cells

Cited by 100 publications

References 37 publications

Landscape of somatic mutations and clonal evolution in mantle cell lymphoma

Landscape of somatic mutations and clonal evolution in mantle cell lymphoma

Venous thromboembolism, interleukin-6 and survival outcomes in patients with advanced ovarian clear cell carcinoma

Interleukin-6 as a Therapeutic Target

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