Publications by authors named "Steffen Boettcher"

26 Publications

  • Page 1 of 1

Effective Menin inhibitor-based combinations against AML with MLL rearrangement or NPM1 mutation (NPM1c).

Blood Cancer J 2022 Jan 11;12(1). Epub 2022 Jan 11.

The University of Texas M.D. Anderson Cancer Center, Houston, TX, 77030, USA.

Treatment with Menin inhibitor (MI) disrupts the interaction between Menin and MLL1 or MLL1-fusion protein (FP), inhibits HOXA9/MEIS1, induces differentiation and loss of survival of AML harboring MLL1 re-arrangement (r) and FP, or expressing mutant (mt)-NPM1. Following MI treatment, although clinical responses are common, the majority of patients with AML with MLL1-r or mt-NPM1 succumb to their disease. Pre-clinical studies presented here demonstrate that genetic knockout or degradation of Menin or treatment with the MI SNDX-50469 reduces MLL1/MLL1-FP targets, associated with MI-induced differentiation and loss of viability. MI treatment also attenuates BCL2 and CDK6 levels. Co-treatment with SNDX-50469 and BCL2 inhibitor (venetoclax), or CDK6 inhibitor (abemaciclib) induces synergistic lethality in cell lines and patient-derived AML cells harboring MLL1-r or mtNPM1. Combined therapy with SNDX-5613 and venetoclax exerts superior in vivo efficacy in a cell line or PD AML cell xenografts harboring MLL1-r or mt-NPM1. Synergy with the MI-based combinations is preserved against MLL1-r AML cells expressing FLT3 mutation, also CRISPR-edited to introduce mtTP53. These findings highlight the promise of clinically testing these MI-based combinations against AML harboring MLL1-r or mtNPM1.
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http://dx.doi.org/10.1038/s41408-021-00603-3DOI Listing
January 2022

CXCL12-abundant reticular cells are the major source of IL-6 upon LPS stimulation and thereby regulate hematopoiesis.

Blood Adv 2021 12;5(23):5002-5015

Department of Medical Oncology and Hematology, University of Zurich and University Hospital Zurich, Zurich, Switzerland.

Hematopoiesis is maintained by hematopoietic stem and progenitor cells that are located in the bone marrow (BM) where they are embedded within a complex supportive microenvironment consisting of a multitude of various non-hematopoietic and hematopoietic cell types. The BM microenvironment not only regulates steady-state hematopoiesis by provision of growth factors, cytokines, and cell-cell contact but is also an emerging key player during the adaptation to infectious and inflammatory insults (emergency hematopoiesis). Through a combination of gene expression analyses in prospectively isolated non-hematopoietic BM cell populations and various mouse models, we found that BM CXCL12-abundant reticular (CAR) cells are a major source of systemic and local BM interleukin-6 (IL-6) levels during emergency hematopoiesis after lipopolysaccharide (LPS) stimulation. Importantly, although IL-6 is dispensable during the initial phase of LPS-induced emergency hematopoiesis, it is required to sustain an adequate hematopoietic output during chronic repetitive inflammation. Our data highlight the essential role of the non-hematopoietic BM microenvironment for the sensing and integration of pathogen-derived signals into sustained demand-adapted hematopoietic responses.
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http://dx.doi.org/10.1182/bloodadvances.2021005531DOI Listing
December 2021

IL-1 mediates microbiome-induced inflammaging of hematopoietic stem cells in mice.

Blood 2022 Jan;139(1):44-58

Department of Medical Oncology and Hematology, University Hospital Zurich, Comprehensive Cancer Center Zurich, University of Zurich, Zurich, Switzerland.

Aging is associated with impaired hematopoietic and immune function caused in part by decreased fitness in the hematopoietic stem cell (HSC) population and an increased myeloid differentiation bias. The reasons for this aging-associated HSC impairment are incompletely understood. Here we demonstrate that older specific pathogen free (SPF) wild-type (WT) mice in contrast to young SPF mice produce more interleukin-1a and interleukin-1b (IL-1a/b) in steady-state bone marrow (BM), with most of the IL-1a/b being derived from myeloid BM cells. Furthermore, blood from steady-state older SPF WT mice contains higher levels of microbe-associated molecular patterns, specifically TLR4 and TLR8 ligands. In addition, BM myeloid cells from older mice produce more IL-1b in vitro, and older mice show higher and more durable IL-1a/b responses upon stimulation with lipopolysaccharide in vivo. To test whether HSC aging is driven by IL-1a/b, we evaluated HSCs from IL-1 receptor 1 (IL-1R1) knockout (KO) mice. Indeed, older HSCs from IL-1R1KO mice show significantly mitigated aging-associated inflammatory signatures. Moreover, HSCs from older IL-1R1KO and from germ-free mice maintain unbiased lymphomyeloid hematopoietic differentiation upon transplantation, thus resembling this functionality of young HSCs. Importantly, in vivo antibiotic suppression of microbiota or pharmacologic blockade of IL-1 signaling in older WT mice was similarly sufficient to reverse myeloid-biased output of their HSC populations. Collectively, our data define the microbiome/IL-1/IL-1R1 axis as a key, self-sustaining and also therapeutically partially reversible driver of HSC inflammaging.
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http://dx.doi.org/10.1182/blood.2021011570DOI Listing
January 2022

Distinct genetic pathways define pre-malignant versus compensatory clonal hematopoiesis in Shwachman-Diamond syndrome.

Nat Commun 2021 02 26;12(1):1334. Epub 2021 Feb 26.

Dartmouth-Hitchcock Medical Center, Pediatric Hematology Oncology, Geisel School of Medicine, Lebanon, NH, USA.

To understand the mechanisms that mediate germline genetic leukemia predisposition, we studied the inherited ribosomopathy Shwachman-Diamond syndrome (SDS), a bone marrow failure disorder with high risk of myeloid malignancies at an early age. To define the mechanistic basis of clonal hematopoiesis in SDS, we investigate somatic mutations acquired by patients with SDS followed longitudinally. Here we report that multiple independent somatic hematopoietic clones arise early in life, most commonly harboring heterozygous mutations in EIF6 or TP53. We show that germline SBDS deficiency establishes a fitness constraint that drives selection of somatic clones via two distinct mechanisms with different clinical consequences. EIF6 inactivation mediates a compensatory pathway with limited leukemic potential by ameliorating the underlying SDS ribosome defect and enhancing clone fitness. TP53 mutations define a maladaptive pathway with enhanced leukemic potential by inactivating tumor suppressor checkpoints without correcting the ribosome defect. Subsequent development of leukemia was associated with acquisition of biallelic TP53 alterations. These results mechanistically link leukemia predisposition to germline genetic constraints on cellular fitness, and provide a rational framework for clinical surveillance strategies.
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http://dx.doi.org/10.1038/s41467-021-21588-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7910481PMC
February 2021

Clonal hematopoiesis in hematopoietic stem cell transplantation.

Curr Opin Hematol 2021 03;28(2):94-100

Department of Medical Oncology and Hematology, University Hospital Zurich and University of Zurich, Zurich, Switzerland.

Purpose Of Review: Clonal hematopoiesis (CH) is characterized by the acquisition of somatic mutations and subsequent expansion of mutated hematopoietic stem and progenitor cell (HSPC) clones without clinical evidence for a hematologic neoplasm. The prevalence of CH continuously increases with age reaching double-digit percentages in individuals >60 years. CH is associated with an increased risk for hematologic neoplasms and cardiovascular disease. We will review recent efforts to investigate how CH influences patient outcomes in hematopoietic stem cell transplantation - both autologous (ASCT) and allogeneic (allo-HSCT).

Recent Findings: Donor-engrafted CH is common in allo-HSCT recipients. Apart from a higher incidence of chronic GvHD and the rare but devastating complication of donor-derived leukemia, CH does not appear to negatively impact outcomes in allo-HSCT recipients. In lymphoma patients undergoing ASCT, however, CH is associated with an excess mortality driven by therapy-related myeloid neoplasms and cardiovascular events. Interestingly, inferior overall survival in patients with CH undergoing ASCT for multiple myeloma (MM) is due to an increased rate of MM progression.

Summary: CH is highly prevalent in both allo-HSCT and ASCT patients suggesting a clinically relevant but context-dependent impact on adverse outcomes. Given the current lack of therapeutic interventions, systematic screening for CH in the transplant setting is currently not indicated outside of clinical studies.
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http://dx.doi.org/10.1097/MOH.0000000000000631DOI Listing
March 2021

Wnt to the rescue! A new role in granulopoiesis.

Blood 2020 11;136(22):2487-2489

University Hospital Zurich.

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http://dx.doi.org/10.1182/blood.2020008667DOI Listing
November 2020

An induced pluripotent stem cell model of Fanconi anemia reveals mechanisms of p53-driven progenitor cell differentiation.

Blood Adv 2020 10;4(19):4679-4692

Stem Cell Program, Boston Children's Hospital, Boston, MA.

Fanconi anemia (FA) is a disorder of DNA repair that manifests as bone marrow (BM) failure. The lack of accurate murine models of FA has refocused efforts toward differentiation of patient-derived induced pluripotent stem cells (IPSCs) to hematopoietic progenitor cells (HPCs). However, an intact FA DNA repair pathway is required for efficient IPSC derivation, hindering these efforts. To overcome this barrier, we used inducible complementation of FANCA-deficient IPSCs, which permitted robust maintenance of IPSCs. Modulation of FANCA during directed differentiation to HPCs enabled the production of FANCA-deficient human HPCs that recapitulated FA genotoxicity and hematopoietic phenotypes relative to isogenic FANCA-expressing HPCs. FANCA-deficient human HPCs underwent accelerated terminal differentiation driven by activation of p53/p21. We identified growth arrest specific 6 (GAS6) as a novel target of activated p53 in FANCA-deficient HPCs and modulate GAS6 signaling to rescue hematopoiesis in FANCA-deficient cells. This study validates our strategy to derive a sustainable, highly faithful human model of FA, uncovers a mechanism of HPC exhaustion in FA, and advances toward future cell therapy in FA.
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http://dx.doi.org/10.1182/bloodadvances.2020001593DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556119PMC
October 2020

TP53 mutations in myelodysplastic syndromes and secondary AML confer an immunosuppressive phenotype.

Blood 2020 12;136(24):2812-2823

Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.

Somatic gene mutations are key determinants of outcome in patients with myelodysplastic syndromes (MDS) and secondary AML (sAML). In particular, patients with TP53 mutations represent a distinct molecular cohort with uniformly poor prognosis. The precise pathogenetic mechanisms underlying these inferior outcomes have not been delineated. In this study, we characterized the immunological features of the malignant clone and alterations in the immune microenvironment in patients with TP53-mutant and wild-type MDS or sAML. Notably, PDL1 expression is significantly increased in hematopoietic stem cells of patients with TP53 mutations, which is associated with MYC upregulation and marked downregulation of MYC's negative regulator miR-34a, a p53 transcription target. Notably, patients with TP53 mutations display significantly reduced numbers of bone marrow-infiltrating OX40+ cytotoxic T cells and helper T cells, as well as decreased ICOS+ and 4-1BB+ natural killer cells. Further, highly immunosuppressive regulatory T cells (Tregs) (ie, ICOShigh/PD-1-) and myeloid-derived suppressor cells (PD-1low) are expanded in cases with TP53 mutations. Finally, a higher proportion of bone marrow-infiltrating ICOShigh/PD-1- Treg cells is a highly significant independent predictor of overall survival. We conclude that the microenvironment of TP53 mutant MDS and sAML has an immune-privileged, evasive phenotype that may be a primary driver of poor outcomes and submit that immunomodulatory therapeutic strategies may offer a benefit for this molecularly defined subpopulation.
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http://dx.doi.org/10.1182/blood.2020006158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7731792PMC
December 2020

Clonal hematopoiesis in donors and long-term survivors of related allogeneic hematopoietic stem cell transplantation.

Blood 2020 04;135(18):1548-1559

Department of Medical Oncology and Hematology, University of Zurich and University Hospital Zurich, Zurich, Switzerland.

Clonal hematopoiesis (CH) is associated with age and an increased risk of myeloid malignancies, cardiovascular risk, and all-cause mortality. We tested for CH in a setting where hematopoietic stem cells (HSCs) of the same individual are exposed to different degrees of proliferative stress and environments, ie, in long-term survivors of allogeneic hematopoietic stem cell transplantation (allo-HSCT) and their respective related donors (n = 42 donor-recipient pairs). With a median follow-up time since allo-HSCT of 16 years (range, 10-32 years), we found a total of 35 mutations in 23 out of 84 (27.4%) study participants. Ten out of 42 donors (23.8%) and 13 out of 42 recipients (31%) had CH. CH was associated with older donor and recipient age. We identified 5 cases of donor-engrafted CH, with 1 case progressing into myelodysplastic syndrome in both donor and recipient. Four out of 5 cases showed increased clone size in recipients compared with donors. We further characterized the hematopoietic system in individuals with CH as follows: (1) CH was consistently present in myeloid cells but varied in penetrance in B and T cells; (2) colony-forming units (CFUs) revealed clonal evolution or multiple independent clones in individuals with multiple CH mutations; and (3) telomere shortening determined in granulocytes suggested ∼20 years of added proliferative history of HSCs in recipients compared with their donors, with telomere length in CH vs non-CH CFUs showing varying patterns. This study provides insight into the long-term behavior of the same human HSCs and respective CH development under different proliferative conditions.
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http://dx.doi.org/10.1182/blood.2019003079DOI Listing
April 2020

Treatment-Induced Tumor Dormancy through YAP-Mediated Transcriptional Reprogramming of the Apoptotic Pathway.

Cancer Cell 2020 01;37(1):104-122.e12

Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Dana-Farber Cancer Institute, Boston, MA 02215, USA.

Eradicating tumor dormancy that develops following epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment of EGFR-mutant non-small cell lung cancer, is an attractive therapeutic strategy but the mechanisms governing this process are poorly understood. Blockade of ERK1/2 reactivation following EGFR TKI treatment by combined EGFR/MEK inhibition uncovers cells that survive by entering a senescence-like dormant state characterized by high YAP/TEAD activity. YAP/TEAD engage the epithelial-to-mesenchymal transition transcription factor SLUG to directly repress pro-apoptotic BMF, limiting drug-induced apoptosis. Pharmacological co-inhibition of YAP and TEAD, or genetic deletion of YAP1, all deplete dormant cells by enhancing EGFR/MEK inhibition-induced apoptosis. Enhancing the initial efficacy of targeted therapies could ultimately lead to prolonged treatment responses in cancer patients.
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http://dx.doi.org/10.1016/j.ccell.2019.12.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7146079PMC
January 2020

Global Transcriptomic Profiling of the Bone Marrow Stromal Microenvironment during Postnatal Development, Aging, and Inflammation.

Cell Rep 2019 12;29(10):3313-3330.e4

Department of Medical Oncology and Hematology, University Hospital and University of Zurich, 8091 Zurich, Switzerland. Electronic address:

Bone marrow (BM) stromal cells provide the regulatory framework for hematopoiesis and contribute to developmental stage-specific niches, such as those preserving hematopoietic stem cells. Despite advances in our understanding of stromal function, little is known about the transcriptional changes that this compartment undergoes throughout lifespan and during adaptation to stress. Using RNA sequencing, we perform transcriptional analyses of four principal stromal subsets, namely CXCL12-abundant reticular, platelet-derived growth factor receptor (PDGFR)-αSca1, sinusoidal, and arterial endothelial cells, from early postnatal, adult, and aged mice. Our data reveal (1) molecular fingerprints defining cell-specific anatomical and functional features, (2) a radical reprogramming of pro-hematopoietic, immune, and matrisomic transcriptional programs during the transition from juvenile stages to adulthood, and (3) the aging-driven progressive upregulation of pro-inflammatory gene expression in stroma. We further demonstrate that transcriptomic pathways elicited in vivo by prototypic microbial molecules are largely recapitulated during aging, thereby supporting the inflammatory basis of age-related adaptations of BM hematopoietic function.
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http://dx.doi.org/10.1016/j.celrep.2019.11.004DOI Listing
December 2019

A dominant-negative effect drives selection of missense mutations in myeloid malignancies.

Science 2019 08;365(6453):599-604

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.

, which encodes the tumor suppressor p53, is the most frequently mutated gene in human cancer. The selective pressures shaping its mutational spectrum, dominated by missense mutations, are enigmatic, and neomorphic gain-of-function (GOF) activities have been implicated. We used CRISPR-Cas9 to generate isogenic human leukemia cell lines of the most common missense mutations. Functional, DNA-binding, and transcriptional analyses revealed loss of function but no GOF effects. Comprehensive mutational scanning of p53 single-amino acid variants demonstrated that missense variants in the DNA-binding domain exert a dominant-negative effect (DNE). In mice, the DNE of p53 missense variants confers a selective advantage to hematopoietic cells on DNA damage. Analysis of clinical outcomes in patients with acute myeloid leukemia showed no evidence of GOF for missense mutations. Thus, a DNE is the primary unit of selection for missense mutations in myeloid malignancies.
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http://dx.doi.org/10.1126/science.aax3649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7327437PMC
August 2019

Clonal Hematopoiesis of Indeterminate Potential.

J Clin Oncol 2019 02 27;37(5):419-422. Epub 2018 Dec 27.

1 Dana-Farber Cancer Institute, Boston, MA.

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http://dx.doi.org/10.1200/JCO.2018.79.3588DOI Listing
February 2019

Regulation of Inflammation- and Infection-Driven Hematopoiesis.

Trends Immunol 2017 05 16;38(5):345-357. Epub 2017 Feb 16.

Hematology, University and University Hospital Zurich, Zurich, Switzerland. Electronic address:

Innate myeloid immune cells, and neutrophils in particular, serve as first line of defense against pathogenic microorganisms including bacteria and fungi. Given their short life span during steady-state conditions, myeloid cells - with, in some cases, the exception of tissue macrophages - need to be constantly regenerated from hematopoietic stem and progenitor cells. During severe systemic bacterial infection, myeloid cell turnover is dramatically increased due to their unique modus operandi in combating invading pathogens involving release of lytic enzymes and neutrophil extracellular traps. Consequently, steady-state hematopoiesis is switched to emergency hematopoiesis by launching a unique hematopoietic response program that is aimed at greatly increasing myeloid cell output to meet the higher demand. In this review, we will discuss well-established as well as recently emerging concepts around the regulation of this fundamental process.
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http://dx.doi.org/10.1016/j.it.2017.01.004DOI Listing
May 2017

LPS-stimulated human bone marrow stroma cells support myeloid cell development and progenitor cell maintenance.

Ann Hematol 2016 Jan 11;95(2):173-8. Epub 2015 Nov 11.

Department of Oncology, Hematology, Hemostaseology and Stem cell transplantation, University Hospital Aachen, RWTH Aachen University, Pauwelsstrasse 30, 52074, Aachen, Germany.

The nonhematopoietic bone marrow (BM) microenvironment provides a functional niche for hematopoietic cell maintenance, recruitment, and differentiation. It consists of multiple cell types including vasculature, bone, adipose tissue, and fibroblast-like bone marrow stromal cells (BMSC), which can be summarized under the generic term niche cells. BMSC express Toll-like receptors (TLRs) and are capable to respond to TLR-agonists by changing their cytokine expression pattern in order to more efficiently support hematopoiesis. Here, we show that in addition to enhanced myeloid colony formation from human CD34+ cells, lipopolysaccharide (LPS) stimulation retains overall higher numbers of CD34+ cells in co-culture assays using BMSC, with eightfold more CD34+ cells that underwent up to three divisions as compared to non-stimulated assays. When subjected to cytokine-supplemented myeloid colony-forming unit (CFU) assays or transplanted into newborn RAG2(-/-) γc (-/-) mice, CD34(+) cells from LPS-stimulated BMSC cultures give rise to the full spectrum of myeloid colonies and T and B cells, respectively, thus supporting maintenance of myeloid and lymphoid primed hematopoietic progenitor cells (HPCs) under inflammatory conditions. Collectively, we suggest that BMSC enhance hematopoiesis during inflammatory conditions to support the replenishment of innate immune effector cells and to prevent the exhaustion of the hematopoietic stem and progenitor cell (HSPC) pool.
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http://dx.doi.org/10.1007/s00277-015-2550-5DOI Listing
January 2016

Sensing and translation of pathogen signals into demand-adapted myelopoiesis.

Curr Opin Hematol 2016 Jan;23(1):5-10

Division of Hematology, University Hospital Zurich, Zurich, Switzerland.

Purpose Of Review: During severe systemic infection, steady-state hematopoiesis is switched to demand-adapted myelopoiesis, leading to increased myeloid progenitor proliferation and, depending on the context and type of pathogen, enhanced granulocytic or monocytic differentiation, respectively. We will review the recent advances in understanding direct and indirect mechanisms by which different pathogen signals are detected and subsequently translated into demand-adapted myelopoiesis.

Recent Findings: Enhanced myeloid progenitor proliferation and neutrophil differentiation following infection with prototypic Gram-negative bacterium Escherichia coli is mediated by granulocyte colony-stimulating factor, and reactive oxygen species released from endothelial cells and mature myeloid cells, respectively. Furthermore, hematopoietic stem and progenitor cells directly sense pathogen signals via Toll-like receptors and contribute to emergency granulopoiesis via release and subsequent autocrine and paracrine action of myelopoietic cytokines including IL-6. Moreover, emergency monocytopoiesis upon viral infection depends on T cell-derived IFNγ and release of IL-6 from bone marrow stromal cells.

Summary: A complex picture is evolving in which various hematopoietic and nonhematopoietic cell types interact with the hematopoietic system in an intricate manner to shape an appropriate hematopoietic response to specific infectious stimuli.
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http://dx.doi.org/10.1097/MOH.0000000000000201DOI Listing
January 2016

DEPDC1/LET-99 participates in an evolutionarily conserved pathway for anti-tubulin drug-induced apoptosis.

Nat Cell Biol 2014 Aug 27;16(8):812-20. Epub 2014 Jul 27.

Institute of Molecular Life Sciences, University of Zurich, Winterthurerstrasse 190 CH-8057 Zurich, Switzerland.

Microtubule-targeting chemotherapeutics induce apoptosis in cancer cells by promoting the phosphorylation and degradation of the anti-apoptotic BCL-2 family member MCL1. The signalling cascade linking microtubule disruption to MCL1 degradation remains however to be defined. Here, we establish an in vivo screening strategy in Caenorhabditis elegans to uncover genes involved in chemotherapy-induced apoptosis. Using an RNAi-based screen, we identify three genes required for vincristine-induced apoptosis. We show that the DEP domain protein LET-99 acts upstream of the heterotrimeric G protein alpha subunit GPA-11 to control activation of the stress kinase JNK-1. The human homologue of LET-99, DEPDC1, similarly regulates vincristine-induced cell death by promoting JNK-dependent degradation of the BCL-2 family protein MCL1. Collectively, these data uncover an evolutionarily conserved mediator of anti-tubulin drug-induced apoptosis and suggest that DEPDC1 levels could be an additional determinant for therapy response upstream of MCL1.
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http://dx.doi.org/10.1038/ncb3010DOI Listing
August 2014

Endothelial cells translate pathogen signals into G-CSF-driven emergency granulopoiesis.

Blood 2014 Aug 2;124(9):1393-403. Epub 2014 Jul 2.

Division of Hematology, University Hospital Zurich, Zurich, Switzerland;

Systemic bacterial infection induces a hematopoietic response program termed "emergency granulopoiesis" that is characterized by increased de novo bone marrow (BM) neutrophil production. How loss of local immune control and bacterial dissemination is sensed and subsequently translated into the switch from steady-state to emergency granulopoiesis is, however, unknown. Using tissue-specific myeloid differentiation primary response gene 88 (Myd88)-deficient mice and in vivo lipopolysaccharide (LPS) administration to model severe bacterial infection, we here show that endothelial cells (ECs) but not hematopoietic cells, hepatocytes, pericytes, or BM stromal cells, are essential cells for this process. Indeed, ECs from multiple tissues including BM express high levels of Tlr4 and Myd88 and are the primary source of granulocyte colony-stimulating factor (G-CSF), the key granulopoietic cytokine, after LPS challenge or infection with Escherichia coli. EC-intrinsic MYD88 signaling and subsequent G-CSF production by ECs is required for myeloid progenitor lineage skewing toward granulocyte-macrophage progenitors, increased colony-forming unit granulocyte activity in BM, and accelerated BM neutrophil generation after LPS stimulation. Thus, ECs catalyze the detection of systemic infection into demand-adapted granulopoiesis.
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http://dx.doi.org/10.1182/blood-2014-04-570762DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4148762PMC
August 2014

A novel mouse model for inhibition of DOHH-mediated hypusine modification reveals a crucial function in embryonic development, proliferation and oncogenic transformation.

Dis Model Mech 2014 Aug 15;7(8):963-76. Epub 2014 May 15.

Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald-Tumor Zentrum, University Hospital Eppendorf, 20246 Hamburg, Germany. Division of Hematology, University Hospital Zurich, 8091 Zurich, Switzerland.

The central importance of translational control by post-translational modification has spurred major interest in regulatory pathways that control translation. One such pathway uniquely adds hypusine to eukaryotic initiation factor 5A (eIF5A), and thereby affects protein synthesis and, subsequently, cellular proliferation through an unknown mechanism. Using a novel conditional knockout mouse model and a Caenorhabditis elegans knockout model, we found an evolutionarily conserved role for the DOHH-mediated second step of hypusine synthesis in early embryonic development. At the cellular level, we observed reduced proliferation and induction of senescence in 3T3 Dohh-/- cells as well as reduced capability for malignant transformation. Furthermore, mass spectrometry showed that deletion of DOHH results in an unexpected complete loss of hypusine modification. Our results provide new biological insight into the physiological roles of the second step of the hypusination of eIF5A. Moreover, the conditional mouse model presented here provides a powerful tool for manipulating hypusine modification in a temporal and spatial manner, to analyse both how this unique modification normally functions in vivo as well as how it contributes to different pathological conditions.
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http://dx.doi.org/10.1242/dmm.014449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4107325PMC
August 2014

Emergency granulopoiesis.

Nat Rev Immunol 2014 May 22;14(5):302-14. Epub 2014 Apr 22.

Division of Hematology, University Hospital Zurich, Raemistrasse 100, CH-8091 Zurich, Switzerland.

Neutrophils are a key cell type of the innate immune system. They are short-lived and need to be continuously generated in steady-state conditions from haematopoietic stem and progenitor cells in the bone marrow to ensure their immediate availability for the containment of invading pathogens. However, if microbial infection cannot be controlled locally, and consequently develops into a life-threatening condition, neutrophils are used up in large quantities and the haematopoietic system has to rapidly adapt to the increased demand by switching from steady-state to emergency granulopoiesis. This involves the markedly increased de novo production of neutrophils, which results from enhanced myeloid precursor cell proliferation in the bone marrow. In this Review, we discuss the molecular and cellular events that regulate emergency granulopoiesis, a process that is crucial for host survival.
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http://dx.doi.org/10.1038/nri3660DOI Listing
May 2014

Endothelial CCR2 signaling induced by colon carcinoma cells enables extravasation via the JAK2-Stat5 and p38MAPK pathway.

Cancer Cell 2012 Jul;22(1):91-105

Institute of Neuropathology, University Hospital Zurich, CH-8091 Zurich, Switzerland.

Increased expression of the chemokine CCL2 in tumor cells correlates with enhanced metastasis, poor prognosis, and recruitment of CCR2(+)Ly6C(hi) monocytes. However, the mechanisms driving tumor cell extravasation through the endothelium remain elusive. Here, we describe CCL2 upregulation in metastatic UICC stage IV colon carcinomas and demonstrate that tumor cell-derived CCL2 activates the CCR2(+) endothelium to increase vascular permeability in vivo. CCR2 deficiency prevents colon carcinoma extravasation and metastasis. Of note, CCR2 expression on radio-resistant cells or endothelial CCR2 expression restores extravasation and metastasis in Ccr2(-/-) mice. Reduction of CCR2 expression on myeloid cells decreases but does not prevent metastasis. CCL2-induced vascular permeability and metastasis is dependent on JAK2-Stat5 and p38MAPK signaling. Our study identifies potential targets for treating CCL2-dependent metastasis.
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http://dx.doi.org/10.1016/j.ccr.2012.05.023DOI Listing
July 2012

Cutting edge: LPS-induced emergency myelopoiesis depends on TLR4-expressing nonhematopoietic cells.

J Immunol 2012 Jun 14;188(12):5824-8. Epub 2012 May 14.

Institute for Research in Biomedicine, 6500 Bellinzona, Switzerland.

Systemic bacterial infection is rapidly recognized as an emergency state leading to neutrophil release into the circulation and increased myeloid cell production within the bone marrow. However, the mechanisms of sensing infection and subsequent translation into emergency myelopoiesis have not been defined. In this study, we demonstrate in vivo in mice that, surprisingly, selective TLR4 expression within the hematopoietic compartment fails to induce LPS-driven emergency myelopoiesis. In contrast, TLR4-expressing nonhematopoietic cells are indispensable for LPS-induced, G-CSF-mediated myelopoietic responses. Furthermore, LPS-induced emergency myelopoiesis is independent of intact IL-1RI signaling and, thus, does not require inflammasome activation. Collectively, our findings reveal a key and nonredundant role for nonhematopoietic compartment pathogen sensing that is subsequently translated into cytokine release for enhanced, demand-adapted myeloid cell production.
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http://dx.doi.org/10.4049/jimmunol.1103253DOI Listing
June 2012

Demand-adapted regulation of early hematopoiesis in infection and inflammation.

Blood 2012 Mar 13;119(13):2991-3002. Epub 2012 Jan 13.

Division of Hematology, University Hospital Zürich, Zürich, Switzerland.

During systemic infection and inflammation, immune effector cells are in high demand and are rapidly consumed at sites of need. Although adaptive immune cells have high proliferative potential, innate immune cells are mostly postmitotic and need to be replenished from bone marrow (BM) hematopoietic stem and progenitor cells. We here review how early hematopoiesis has been shaped to deliver efficient responses to increased need. On the basis of most recent findings, we develop an integrated view of how cytokines, chemokines, as well as conserved pathogen structures, are sensed, leading to divisional activation, proliferation, differentiation, and migration of hematopoietic stem and progenitor cells, all aimed at efficient contribution to immune responses and rapid reestablishment of hematopoietic homeostasis. We also outline how chronic inflammatory processes might impinge on hematopoiesis, potentially fostering hematopoietic stem cell diseases, and, how clinical benefit is and could be achieved by learning from nature.
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http://dx.doi.org/10.1182/blood-2011-12-380113DOI Listing
March 2012

Acquired coagulopathy caused by intoxication with the superwarfarin-type anticoagulant rodenticide flocoumafen.

Eur J Haematol 2011 Feb 29;86(2):173-5. Epub 2010 Dec 29.

Department of Hematology/Oncology, University of Tuebingen Medical School, Otfried-Mueller-Strasse 10, Tuebingen, Germany.

A 28 year-old heretofore healthy woman was transferred to our hospital with a two-month history of recurring episodes of bleeding. Administration of vitamin K and prothrombin complex concentrates in the transferring hospital had only temporarily corrected both the markedly elevated international normalized ratio (INR) and the prolonged activated partial thromboplastin time (aPTT). The patient's medical and family history revealed no reason for these abnormalities. Our laboratory analyses revealed a sustained deficiency of vitamin K-dependent clotting factors. Presence of an acquired inhibitor of clotting factors was excluded. Thus we suspected, intoxication with an anticoagulant rodenticide. Liquid chromatography-mass spectrometry (LC-MS/MS) revealed pharmacologically active concentrations of flocoumafen, a rodenticide belonging to the superwarfarin family, in the patient's serum. While the long elimination half-life of superwarfarins is well described in rodents, information on pharmacokinetics in humans is not yet available. Therefore, patient management was not limited to prolonged administration of vitamin K, but also included repeated measurements of flocoumafen serum levels. During follow-up visits, clotting tests remained normal and flocoumafen levels gradually decreased, reaching the limit of quantification after 48 days. Based on the repeated measurements of flocoumafen serum levels, a half-life of 6.7 days was estimated in our patient, which is in clear contrast to the 220 days reported in rodents. Thus, monitoring flocoumafen serum concentrations in affected patients may provide a rational basis for the duration of vitamin K substitution and adequate follow-up intervals.
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http://dx.doi.org/10.1111/j.1600-0609.2010.01550.xDOI Listing
February 2011
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