LYN Kinase in the Tumor Microenvironment Is Essential for the Progression of Chronic Lymphocytic Leukemia

Nguyen, Phuong-Hien; Fedorchenko, Oleg; Rosen, Natascha; Koch, Maximilian; Barthel, Romy; Winarski, Tomasz; Florin, Alexandra; Wunderlich, Frank; Reinart, Nina; Hallek, Michael

doi:10.1016/j.ccell.2016.09.007

Cited by 73 publications

(77 citation statements)

References 72 publications

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“…As chemokine secretion may entail a selection advantage for malignant B cells in vivo, its dependence on BTK activity could favour mutations at cysteine 481 in clinically acquired ibrutinib resistance. Our demonstration of maintained chemokine secretion in the presence of ibrutinib owing to the BTK‐C481S mutation reconciles the selection of resistance mutations in malignant B cells exhibiting acquired ibrutinib resistance (Woyach et al , ) with prevalent contributions of accessory cells to the roles of BTK and LYN in CLL pathogenesis (Nguyen et al , ).…”

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confidence: 78%

Establishing a chemical genetic link between Bruton tyrosine kinase activity in malignant B cells and cell functions involved in the micro‐environmental dialogue

et al. 2017

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To elucidate their mechanism of action, inhibitors of Bruton tyrosine kinase (BTK) and resistant BTK mutants were employed to dissect target-dependent cellular functions. BTK-C481S and -T474I, expressed in Ramos and NALM-6 cells, maintained BTK auto-phosphorylation under treatment with ibrutinib or dasatinib, respectively, which showed only modest cytotoxicity. Retained activity of BTK-T474 partially rescued cell migration from inhibition by dasatinib. Importantly, resistant BTK mutants reconstituted B cell receptor-triggered chemokine secretion in the presence of corresponding inhibitors, demonstrating that BTK activity is connected with cell-intrinsic functions of malignant B cells with importance for their dialogue with the micro-environment.

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confidence: 78%

Establishing a chemical genetic link between Bruton tyrosine kinase activity in malignant B cells and cell functions involved in the micro‐environmental dialogue

et al. 2017

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“…In a murine model of chronic lymphocytic leukemia (CLL), transplantation of CLL cells into mice deficient for the Lyn kinase or Bruton's tyrosine kinase (BTK) led to a decelerated leukemia progression and prolonged survival, suggesting that Lyn and BTK in the BMM are essential for leukemic progression in CLL. Interestingly, Lyn deficiency in macrophages, which exert a 'nursing' function for CLL cells through direct cell-cell contact, were implicated in the observed phenotype (Nguyen et al, 2016) (see poster).…”

Section: Cell Adhesion Molecules and Other Niche Components Involved mentioning

confidence: 99%

The bone marrow microenvironment in health and disease at a glance

Kumar

Godavarthy

Krause

2018

Journal of Cell Science

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The bone marrow microenvironment (BMM) is the 'domicile' of hematopoietic stem cells, as well as of malignant processes that can develop there. Multiple and complex interactions with the BMM influence hematopoietic stem cell (HSC) physiology, but also the pathophysiology of hematological malignancies. Reciprocally, hematological malignancies alter the BMM, in order to render it more hospitable for malignant progression. In this Cell Science at a Glance article and accompanying poster, we highlight concepts of the normal and malignant hematopoietic stem cell niches. We present the intricacies of the BMM in malignancy and provide approaches for targeting the interactions between malignant cells and their BMM. This is done in an effort to augment existing treatment strategies in the future.

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“…1 – 4 showed that Lyn can efficiently phosphorylate ROR1 that can be subsequently recognized by c-CBL. ROR1 and Lyn are important regulators of signaling pathways driving chronic lymphocytic leukemia (CLL) 1,8,21,35 and several lymphomas, namely mantle cell lymphoma (MCL) 15 . Both, Lyn and ROR1, have been evaluated as therapeutic targets in these malignancies and the understanding of their mutual cross talk is thus of direct therapeutic relevance.…”

Section: Resultsmentioning

confidence: 99%

Lyn controls chemotaxis and motility of CLL cells via phosphorylation of ROR1

Dave

Vondalova-Blanarova

Čada

et al. 2020

Preprint

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word count: 168 words 26 Main text word count: 4183 words 27 Number of Figures: 6 28 Number of tables: 2 29 Running title: Lyn controls chemotaxis and motility of CLL cells via phosphorylation of ROR1.30 Abstract 33 Chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) are malignancies 34 characterized by the dependence on B-cell receptor (BCR) signaling and by the high 35 expression of the cell surface receptor ROR1. Both, BCR and ROR1 are therapeutic targets 36 in these diseases and the understanding of their mutual cross talk is thus of direct 37 therapeutic relevance. In this study we analyzed the role of Lyn, a kinase from the Src 38 family, as a mediator of the BCR-ROR1 crosstalk. We confirm the functional interaction 39 between Lyn and ROR1 and demonstrate that Lyn kinase efficiently phosphorylates ROR1 40 in its kinase domain and aids the recruitment of an E3 ligase c-CBL. The absence of Lyn in 41 Lyn KO Maver-1 cells produced by CRISPR-Cas9 resulted in the increased ROR1 cell 42 surface levels and deregulated migratory properties. Similar correlations between ROR1 43 surface dynamics, levels of active Lyn and chemotactic properties were confirmed in primary 44 CLL samples. Our data establish Lyn-mediated phosphorylation of ROR1 as a point of 45 crosstalk between BCR and ROR1 signaling pathways. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 3 Introduction 60The ROR protein family comprises of ROR1 and ROR2, which are both type 1 61 transmembrane receptors. Upon discovery, ROR proteins were referred to as orphan 62 receptors on account of the lack of identity of their ligands. However, subsequent studies 63 identified their ligands to be the Wnt proteins, mostly Wnt-5a protein 1,2 . Wnt-5a/ROR 64 pathway is an essential signaling pathway that controls cell polarity and migration during 65 embryonic development and tissue homeostasis 3,4 . During embryonic development, RORs 66 are highly and uniformly expressed, most prominently in the skeletal and neural tissues, but 67 postnatally their expression becomes highly restricted 5 . 68Interestingly, ROR1 or ROR2 upregulation has been observed in many cancers: 69ROR1 is upregulated in solid tumors or hematologic malignancies while ROR2 is 70 overexpressed in osteosarcomas or renal cell carcinomas 6 . High expression of ROR1 is 71 typical for some B-cell lymphomas such as mantle cell lymphoma (MCL) 7 and chronic 72 lymphocytic leukemia(CLL) 8,9 . CLL is a form of hematologic cancer which is manifested as a 73 steady accumulation of mature CD5 + B-cells in the bone marrow, lymphoid tissues and 74 peripheral blood. It is the most common form of adult leukemia in the western hemisphere, 75with an incidence of 5 per 100 000 each year and an average median age of on-set around 76 70 years. Most of the CLL cases remain asymptomatic for a long time, in which case 77 therapeutic intervention is not necessary. However, part of the CLL cases progress rapidly, 78 require treatment and their overall life expectancy is decreased 10 . 79CLL cells are in most cases hig...

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LYN Kinase in the Tumor Microenvironment Is Essential for the Progression of Chronic Lymphocytic Leukemia

Cited by 73 publications

References 72 publications

Establishing a chemical genetic link between Bruton tyrosine kinase activity in malignant B cells and cell functions involved in the micro‐environmental dialogue

Establishing a chemical genetic link between Bruton tyrosine kinase activity in malignant B cells and cell functions involved in the micro‐environmental dialogue

The bone marrow microenvironment in health and disease at a glance

Lyn controls chemotaxis and motility of CLL cells via phosphorylation of ROR1

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