Macrophages confer survival signals via CCR1-dependent translational MCL-1 induction in chronic lymphocytic leukemia

Attekum, Martijn H. A. van; Terpstra, Sanne; Slinger, Erik; Lindern, Marieke von; Moerland, Perry D.; Jongejan, Aldo; Kater, Arnon P.; Eldering, Eric

doi:10.1038/onc.2016.515

Cited by 23 publications

(23 citation statements)

References 46 publications

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“…In the first place, we focused on the cell-autonomous response of the CLL cells towards BIRD-2. However, interactions with bystander cells in micro-environmental niches support CLL cells by providing survival and proliferative signals [37][38][39]. Hence, these unsupported experiments were restricted towards short-term BIRD-2 application to limit spontaneous cell death, correlating with loss of Bcl-2-family members such as Table 1).…”

Section: Discussionmentioning

confidence: 99%

“…In the dot plots, each CLL sample is represented with a different color, which is shown in the titles of the individual bar graphs. Statistically significant differences were determined using a one-tailed paired t-test (**P < 0.01) anti-apoptotic Mcl-1 due to rapid loss of supportive signals [37]. Therefore, we also performed experiments in CLL cells supported by CD40L-expressing fibroblasts.…”

Section: Discussionmentioning

confidence: 99%

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Constitutive IP3 signaling underlies the sensitivity of B-cell cancers to the Bcl-2/IP3 receptor disruptor BIRD-2

et al. 2018

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Anti-apoptotic Bcl-2 proteins are upregulated in different cancers, including diffuse large B-cell lymphoma (DLBCL) and chronic lymphocytic leukemia (CLL), enabling survival by inhibiting pro-apoptotic Bcl-2-family members and inositol 1,4,5-trisphosphate (IP 3 ) receptor (IP 3 R)-mediated Ca 2+ -signaling. A peptide tool (Bcl-2/IP 3 R Disruptor-2; BIRD-2) was developed to abrogate the interaction of Bcl-2 with IP 3 Rs by targeting Bcl-2′s BH4 domain. BIRD-2 triggers cell death in primary CLL cells and in DLBCL cell lines. Particularly, DLBCL cells with high levels of IP 3 R2 were sensitive to BIRD-2. Here, we report that BIRD-2-induced cell death in DLBCL cells does not only depend on high IP 3 R2-expression levels, but also on constitutive IP 3 signaling, downstream of the tonically active B-cell receptor. The basal Ca 2+ level in SU-DHL-4 DLBCL cells was significantly elevated due to the constitutive IP 3 production. This constitutive IP 3 signaling fulfilled a prosurvival role, since inhibition of phospholipase C (PLC) using U73122 (2.5 µM) caused cell death in SU-DHL-4 cells. Milder inhibition of IP 3 signaling using a lower U73122 concentration (1 µM) or expression of an IP 3 sponge suppressed both BIRD-2-induced Ca 2+ elevation and apoptosis in SU-DHL-4 cells. Basal PLC/IP 3 signaling also fulfilled a pro-survival role in other DLBCL cell lines, including Karpas 422, RI-1 and SU-DHL-6 cells, whereas PLC inhibition protected these cells against BIRD-2-evoked apoptosis. Finally, U73122 treatment also suppressed BIRD-2-induced cell death in primary CLL, both in unsupported systems and in co-cultures with CD40L-expressing fibroblasts. Thus, constitutive IP 3 signaling in lymphoma and leukemia cells is not only important for cancer cell survival, but also represents a vulnerability, rendering cancer cells dependent on Bcl-2 to limit IP 3 R activity. BIRD-2 seems to switch constitutive IP 3 signaling from pro-survival into pro-death, presenting a plausible therapeutic strategy.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Constitutive IP3 signaling underlies the sensitivity of B-cell cancers to the Bcl-2/IP3 receptor disruptor BIRD-2

et al. 2018

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“…These pro-survival signals result in a nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-dependent upregulation of B-cell lymphoma 2 (BCL2) family members BCL2-related protein A1 (BFL-1) and B-cell lymphoma-extra large (BCL-X L ), 20 and protein kinase B (AKT)-dependent upregulation of induced myeloid leukemia cell differentiation protein (MCL-1). 21 With respect to CLL proliferation, mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription (STAT)3 pathways play additional roles. 22…”

Section: Introductionmentioning

confidence: 99%

“… 56 We recently found that MDC-mediated survival depended on chemokine signaling via CCR1. 21 Nurse-like cells are monocyte-derived cells which develop following prolonged in vitro culture with CLL cells 55 and have been identified in both the spleen and lymph nodes of CLL patients. 57 Nurse-like cells are thought to induce CLL survival effects via factors such as A proliferation inducing ligand (APRIL), B-cell activating factor (BAFF) or C-X-C motif chemokine (CXCL)12 (reviewed by Ten Hacken & Burger 1 ).…”

Section: Introductionmentioning

confidence: 99%

Chronic lymphocytic leukemia cells are active participants in microenvironmental cross-talk

2017

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The importance of the tumor microenvironment in chronic lymphocytic leukemia is widely accepted. Nevertheless, the understanding of the complex interplay between the various types of bystander cells and chronic lymphocytic leukemia cells is incomplete. Numerous studies have indicated that bystander cells provide chronic lymphocytic leukemia-supportive functions, but it has also become clear that chronic lymphocytic leukemia cells actively engage in the formation of a supportive tumor microenvironment through several cross-talk mechanisms. In this review, we describe how chronic lymphocytic leukemia cells participate in this interplay by inducing migration and tumor-supportive differentiation of bystander cells. Furthermore, chronic lymphocytic leukemia-mediated alterations in the interactions between bystander cells are discussed. Upon bystander cell interaction, chronic lymphocytic leukemia cells secrete cytokines and chemokines such as migratory factors [chemokine (C-C motif) ligand 22 and chemokine (CC motif) ligand 2], which result in further recruitment of T cells but also of monocyte-derived cells. Within the tumor microenvironment, chronic lymphocytic leukemia cells induce differentiation towards a tumor-supportive M2 phenotype of monocyte-derived cells and suppress phagocytosis, but also induce increased numbers of supportive regulatory T cells. Like other tumor types, the differentiation of stromal cells towards supportive cancer-associated fibroblasts is critically dependent on chronic lymphocytic leukemia-derived factors such as exosomes and platelet-derived growth factor. Lastly, both chronic lymphocytic leukemia and bystander cells induce a tolerogenic tumor microenvironment; chronic lymphocytic leukemia-secreted cytokines, such as interleukin-10, suppress cytotoxic T-cell functions, while chronic lymphocytic leukemia-associated monocyte-derived cells contribute to suppression of T-cell function by producing the immune checkpoint factor, programmed cell death-ligand 1. Deeper understanding of the active involvement and cross-talk of chronic lymphocytic leukemia cells in shaping the tumor microenvironment may offer novel clues for designing therapeutic strategies.

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“…A relatively new therapeutic target in CLL is colony-stimulating factor 1R (CSF1R), expressed on tumor-associated macrophages (TAMs), and macrophage killing by CSF1R blockade induces CLL cell death, primarily through the tumor necrosis factor pathway 128 . TAMs provide support to CLL cells via a PI3K-AKT-mammalian target of rapamycin (mTOR)-dependent translational upregulation of MCL-1 129 . Both small-molecule kinase inhibitors (for example, pexidartinib 130 and BLZ945 131 ) and monoclonal antibodies targeting CSF1R are in development for various tumor types.…”

Section: Emerging Drug Targetsmentioning

confidence: 99%

Recent therapeutic advances in chronic lymphocytic leukemia

Bose

Gandhi

2017

F1000Res

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The last several years have witnessed a paradigm shift in the management of patients with chronic lymphocytic leukemia (CLL). The course of this very heterogeneous disease, traditionally treated with chemotherapeutic agents usually in combination with rituximab, typically has been characterized by remissions and relapses, and survival times vary greatly, depending on intrinsic biological attributes of the leukemia. The developments of the last few years have been transformative, ushering in an era of novel, molecularly targeted therapies, made possible by extensive efforts to elucidate the biology of the disease that predated the new targeted drugs. Thus, successful therapeutic targeting of the B-cell receptor signaling pathway and of the Bcl-2 anti-apoptotic protein with small molecules has now made chemotherapy-free approaches possible, hopefully mitigating the risk of development of therapy-related myeloid neoplasms and making eventual cure of CLL with the use of optimal drug combinations a realistic goal. Most importantly, these therapies have demonstrated unprecedented efficacy in patients with deletion 17p/TP53 mutation, a subset that historically has been very difficult to treat. However, as we gain more experience with the newer agents, unique safety concerns and resistance mechanisms have emerged, as has the issue of cost, as these expensive drugs are currently administered indefinitely. Accordingly, novel laboratory-based strategies and clinical trial designs are being explored to address these issues. The availability of whole exome/genome sequencing has given us profound insights into the mutational landscape of CLL. In this article, we highlight some of the most impactful advances since this topic was last reviewed in this journal.

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Macrophages confer survival signals via CCR1-dependent translational MCL-1 induction in chronic lymphocytic leukemia

Cited by 23 publications

References 46 publications

Constitutive IP3 signaling underlies the sensitivity of B-cell cancers to the Bcl-2/IP3 receptor disruptor BIRD-2

Constitutive IP3 signaling underlies the sensitivity of B-cell cancers to the Bcl-2/IP3 receptor disruptor BIRD-2

Chronic lymphocytic leukemia cells are active participants in microenvironmental cross-talk

Recent therapeutic advances in chronic lymphocytic leukemia

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