The CXCR4–STAT3–IL-10 Pathway Controls the Immunoregulatory Function of Chronic Lymphocytic Leukemia and Is Modulated by Lenalidomide

Shaim, Hila; Estrov, Zeev; Harris, David; Sanabria, Mayra Hernandez; Liu, Zhiming; Ruvolo, Peter P.; Thompson, P. A.; Ferrajoli, Alessandra; Daher, May; Burger, Jan A.; Müftüoğlu, Muharrem; Imahashi, Nobuhiko; Li, Li; Liu, Enli; Alsuliman, Abdullah; Basar, Rafet; Kerbauy, Lucila Nassif; Sobieski, Catherine; Gokdemir, Elif; Kondo, Kimie; Wierda, William G.; Keating, Michael A.; Shpall, Elizabeth J.; Rezvani, Katayoun

doi:10.3389/fimmu.2017.01773

Cited by 30 publications

(20 citation statements)

References 55 publications

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“…In acute myeloid leukemia cells, murine plasmacytomas, and hybridomas, the autocrine secretion of interleukin-6 caused phosphorylation of STAT3, Tyr705 and Ser727 (9,26), including STAT3-mediated constitutive expression of SOCS-3 in cutaneous T-cell lymphoma (27). In addition, STAT3 also plays a pivotal role in the progression of hematological malignancies, including CLL (28)(29)(30). In the present study, our results revealed that pSTAT3 expression was elevated in PBMCs from CLL patients.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of IL-9 induced by STAT3 phosphorylation is mediated by miR-155 and miR-21 in chronic lymphocytic leukemia

Chen

et al. 2018

Oncol Rep

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Interleukin‑9 (IL‑9) can function as both a positive and negative regulator of immune response, however the role of IL‑9 in tumor immunity is poorly understood. Chronic lymphocytic leukemia (CLL) is the most common chronic lympho‑proliferative disorder. Twenty CLL patients from 2010 to 2011 were recruited in the study. Expression and phosphorylation of transcription factor STAT3 and differential microRNAs (miRs) in peripheral blood mononuclear cells (PBMCs) from CLL patient samples were analyzed. In a previous study, we found a high level of IL‑9 in CLL patients. Concomitantly, overexpression of pSTAT3, miR‑155, and miR‑21 were observed in PBMCs from CLL patients in the present study. To elucidate whether there was interaction among IL‑9, STAT3, miR‑155, and miR‑21, MEC‑1 cells were used for further study. Our results revealed that there was no detectable IL‑9 in the culture medium of MEC‑1 cells. However, the IL‑9 protein could be detected using western blotting in MEC‑1 cells. Notably, when recombinant human IL‑9 (rIL‑9) was added to the medium of culturing MEC‑1 cells, the expression levels of pSTAT3 and IL‑9 in MEC‑1 cells were increased in a time‑dependent manner, which could be blocked by STAT3 inhibitor. Both miR‑155 and miR‑21 could increase IL‑9 expression, which could also be suppressed by the inhibitor of STAT3. Our data indicated that the existence of the novel 'extracellular IL‑9/pSTAT3/miR‑155/miR‑21/intracellular IL‑9' positive feedback system in CLL cells, provides a novel insight in the pathogenesis and possible therapeutic strategy of CLL.

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Section: Discussionmentioning

confidence: 99%

Overexpression of IL-9 induced by STAT3 phosphorylation is mediated by miR-155 and miR-21 in chronic lymphocytic leukemia

Chen

et al. 2018

Oncol Rep

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“…In hematological malignancies, as well as in solid tumors, the overexpression of CXCR4 is responsible for metastasis in organs expressing high CXCL12 levels (e.g., lymph nodes and BM), in addition to disease progression, increased tumor cell survival, and chemoresistance [98]. In chronic lymphocytic leukemia (CLL), the CXCL12/CXCR4 axis induces immune suppression via Signal Transducer and Activator of Transcription 3 (STAT3) phosphorylation in B and T-CLL cells [99]. Recently, p66Shc was identified as a negative regulator of CXCR4 endosome recycling in CLL [100].…”

Section: Cxcl12/cxcr4 Axis In Hematological Tumors: a Crucial Hub Formentioning

confidence: 99%

New Insights on the Emerging Genomic Landscape of CXCR4 in Cancer: A Lesson from WHIM

et al. 2020

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Deciphering the molecular alterations leading to disease initiation and progression is currently crucial to identify the most relevant targets for precision therapy in cancer patients. Cancers express a complex chemokine network influencing leucocyte infiltration and angiogenesis. Moreover, malignant cells also express a selective repertoire of chemokine receptors that sustain their growth and spread. At present, different cancer types have been shown to overexpress C-X-C chemokine receptor type 4 (CXCR4) and to respond to its ligand C-X-C motif chemokine 12 (CXCL12). The CXCL12/CXCR4 axis influences cancer biology, promoting survival, proliferation, and angiogenesis, and plays a pivotal role in directing migration of cancer cells to sites of metastases, making it a prognostic marker and a therapeutic target. More recently, mutations in the C-terminus of CXCR4 have been identified in the genomic landscape of patients affected by Waldenstrom’s macroglobulinemia, a rare B cell neoplasm. These mutations closely resemble those occurring in Warts, Hypogammaglobulinemia, Immunodeficiency, and Myelokathexis (WHIM) syndrome, an immunodeficiency associated with CXCR4 aberrant expression and activity and with chemotherapy resistance in clinical trials. In this review, we summarize the current knowledge on the relevance of CXCR4 mutations in cancer biology, focusing on its importance as predictors of clinical presentation and response to therapy.

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“…Further, STAT3 regulates cytokine production in CLL cells. STAT3 was found to regulate the secretion of IL-9 and IL-10 in CLL cells [18,30]. STAT3-mediated translational upregulation of miR-155 and miR-21 promoted IL-9 secretion [18].…”

Section: Effect Of Stat3 On Cll Cell Metabolismmentioning

confidence: 99%

“…STAT3-mediated translational upregulation of miR-155 and miR-21 promoted IL-9 secretion [18]. Concerning IL-10, the CXCL12-CXCR4-STAT3 axis regulates IL-10 production in CLL cells and their ability to suppress T-cell effector function [30].…”

Section: Effect Of Stat3 On Cll Cell Metabolismmentioning

confidence: 99%

The Important Role of STAT3 in Chronic Lymphocytic Leukaemia Biology

Boudný¹,

Trbušek²

2020

Klin Onkol

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Background:Signal transducer and activator of transcription (STAT) proteins are cytoplasmic transcription factors that transmit the signal of cytokines, hormones and growth factors. STAT proteins control fundamental cellular processes including survival, proliferation and differentiation. Inappropriate activation of STATs might contribute to cellular transformation and leukaemogenesis. About 70% of all solid and haematological tumours exhibit aberrant STAT3 expression and/ or activation, highlighting its essential role in tumourigenesis. Aberrant STAT3 activation has been found in several solid tumours and haematologic malignancies. Importantly, constitutive activation of STAT proteins has been found in several leukaemias including acute myeloid leukaemia, acute promyelocytic leukaemia, acute lymphoblastic leukaemia, chronic myeloid leukaemia and chronic lymphocytic leukaemia (CLL). Constitutively activated STAT3 plays an important role in CLL bio logy. CLL cells harbour constitutive phosphorylation on S727 and acetylation on K685 and transient phosphorylation on Y705 residues. Moreover, STAT3 messenger RNA expression is significantly higher in CLL cells compared to healthy B-lymphocytes. Interestingly, STAT3 inhibition was disclosed as an important by-product of ibrutinib treatment in CLL patients. Purpose: The purpose of this review is to describe the consequences of STAT3 dysregulation in CLL cells. Here, we discuss aberrantly modified processes by STAT3 activation in CLL cells such as proliferation, apoptosis, B cell receptor signalling, cytokine secretion, immune checkpoint regulation, microRNA regulation, free fatty acid metabolism and electron transport chain in the mitochondria. SouhrnVýchodiska: Proteiny STAT (signal transducer and activator of transcription) jsou cytoplazmatické transkripční faktory, které přenášejí signál cytokinů, hormonů a růstových faktorů. Proteiny STAT kontrolují základní buněčné procesy vč. přežití, proliferace a diferenciace. Nadměrná aktivace proteinů STAT může přispět k transformaci buněk a vzniku leukemie. Okolo 70 % všech solidních a hematologických nádorů vykazuje aberantní expresi a/ nebo aktivaci STAT3, což dokumentuje zásadní roli STAT3 v tumorigenezi. Aberantní aktivace STAT3 byla popsána u několika solidních nádorů a hematologických malignit. Důležité je, že konstitutivní aktivace proteinů STAT byla detekována u několika typů leukemie vč. akutní myeloidní leukemie, akutní promyelocytární leukemie, akutní lymfoblastické leukemie, chronické myeloidní leukemie a chronické lymfocytární leukemie (CLL). Konstitutivně aktivovaný STAT3 hraje důležitou roli v bio logii CLL. Buňky CLL jsou konstitutivně fosforylované na S727 a acetylované na K685, navíc může dojít i k fosforylaci na Y705. Exprese mediátorové RNA STAT3 je výrazně vyšší v buňkách CLL ve srovnání se zdravými B lymfocyty. Zajímavé je, že inhibice STAT3 byla popsána jako důležitý vedlejší produkt léčby ibrutinibem u pacientů s CLL. Cíl: Účelem tohoto přehledu je popsat důsledky deregulace STAT3 u buněk CLL. V práci j...

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The CXCR4–STAT3–IL-10 Pathway Controls the Immunoregulatory Function of Chronic Lymphocytic Leukemia and Is Modulated by Lenalidomide

Cited by 30 publications

References 55 publications

Overexpression of IL-9 induced by STAT3 phosphorylation is mediated by miR-155 and miR-21 in chronic lymphocytic leukemia

Overexpression of IL-9 induced by STAT3 phosphorylation is mediated by miR-155 and miR-21 in chronic lymphocytic leukemia

New Insights on the Emerging Genomic Landscape of CXCR4 in Cancer: A Lesson from WHIM

The Important Role of STAT3 in Chronic Lymphocytic Leukaemia Biology

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