Internal organs heal injuries with new connective tissue, but the cellular and molecular events of this process remain obscure. By tagging extracellular matrix around the mesothelium lining in mouse peritoneum, liver and cecum, here we show that preexisting matrix was transferred across organs into wounds in various injury models. Using proteomics, genetic lineage-tracing and selective injury in juxtaposed organs, we found that the tissue of origin for the transferred matrix likely dictated the scarring or regeneration of the healing tissue. Single-cell RNA sequencing and genetic and chemical screens indicated that the preexisting matrix was transferred by neutrophils dependent on the HSF–integrin AM/B2-kindlin3 cascade. Pharmacologic inhibition of this axis prevented matrix transfer and the formation of peritoneal adhesions. Matrix transfer was thus an early event of wound repair and provides a therapeutic window to dampen scaring across a range of conditions.

Acute myeloid leukemia (AML) is a highly heterogeneous malignancy of the blood and bone marrow, characterized by clonal expansion of myeloid stem and progenitor cells and rapid disease progression. Chemotherapy has been the first-line treatment for AML for more than 30 years. Application of recent high-throughput next-generation sequencing technologies has revealed significant molecular heterogeneity to AML, which in turn has motivated efforts to develop new, targeted therapies. However, due to the high complexity of this disease, including multiple driver mutations and the coexistence of multiple competing tumorigenic clones, the successful incorporation of these new agents into clinical practice remains challenging. These continuing difficulties call for the identification of innovative therapeutic approaches that are effective for a larger cohort of AML patients. Recent studies suggest that chronic immune stimulation and aberrant cytokine signaling act as triggers for AML initiation and progression, facets of the disease which might be exploited as promising targets in AML treatment. However, despite the greater appreciation of cytokine profiles in AML, the exact functions of cytokines in AML pathogenesis are not fully understood. Therefore, unravelling the molecular basis of the complex cytokine networks in AML is a prerequisite to develop new therapeutic alternatives based on targeting cytokines and their receptors.

Key Points: Motility of resting CLL cells requires chemokine-mediated RhoA activation but is independent of Tiam1/Rac signals. Tiam1/Rac signals are indispensible for CLL cell proliferation and chemoresistance.

Anaplastic large cell lymphoma (ALCL) is a rare, aggressive, non‐Hodgkin's lymphoma that is characterized by CD30 expression and disease onset in young patients. About half of ALCL patients bear the t(2;5)(p23;q35) translocation, which results in the formation of the nucleophosmin‐anaplastic lymphoma tyrosine kinase (NPM–ALK) fusion protein (ALCL ALK⁺). However, little is known about the molecular features and tumour drivers in ALK‐negative ALCL (ALCL ALK⁻), which is characterized by a worse prognosis. We found that ALCL ALK⁻, in contrast to ALCL ALK⁺, lymphomas display high miR‐155 expression. Consistent with this, we observed an inverse correlation between miR‐155 promoter methylation and miR‐155 expression in ALCL. However, no direct effect of the ALK kinase on miR‐155 levels was observed. Ago2 immunoprecipitation revealed miR‐155 as the most abundant miRNA, and enrichment of target mRNAs C/EBPβ and SOCS1. To investigate its function, we over‐expressed miR‐155 in ALCL ALK⁺ cell lines and demonstrated reduced levels of C/EBPβ and SOCS1. In murine engraftment models of ALCL ALK⁻, we showed that anti‐miR‐155 mimics are able to reduce tumour growth. This goes hand‐in‐hand with increased levels of cleaved caspase‐3 and high SOCS1 in these tumours, which leads to suppression of STAT3 signalling. Moreover, miR‐155 induces IL‐22 expression and suppresses the C/EBPβ target IL‐8. These data suggest that miR‐155 can act as a tumour driver in ALCL ALK⁻ and blocking miR‐155 could be therapeutically relevant. Original miRNA array data are to be found in the supplementary material (Table S1). © 2015 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Neutrophil adhesion and extravasation into tissue at sites of injury or infection depend on binding of the integrin lymphocyte function–associated antigen 1 (LFA-1) to ICAM-1 expressed on activated endothelial cells. The activation-dependent conformational change of LFA-1 to the high-affinity conformation (H+) requires kindlin-3 binding to the β2-integrin cytoplasmic domain. Here we show that genetic deletion of the known kindlin interactor integrin-linked kinase (ILK) impaired neutrophil adhesion and extravasation in the cremaster muscle and in a clinically relevant model of renal ischemia reperfusion injury. Using in vitro microfluidic adhesion chambers and conformation-specific antibodies, we show that knockdown of ILK in HL-60 cells reduced the conformational change of β2-integrins to the H+ conformation. Mechanistically, we found that ILK was required for protein kinase C (PKC) membrane targeting and chemokine-induced upregulation of its kinase activity. Moreover, PKC-α deficiency also resulted in impaired leukocyte adhesion in bone marrow chimeric mice. Mass spectrometric and western blot analyses revealed stimulation- and ILK-dependent phosphorylation of kindlin-3 upon activation. In summary, our data indicate an important role of ILK in kindlin-3–dependent conformational activation of LFA-1.

Leukemia is one of the leading journals in hematology and oncology. It is published monthly and covers all aspects of the research and treatment of leukemia and allied diseases. Studies of normal hemopoiesis are covered because of their comparative relevance.