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1.
Cell ; 185(7): 1223-1239.e20, 2022 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-35290801

RESUMO

While CRISPR screens are helping uncover genes regulating many cell-intrinsic processes, existing approaches are suboptimal for identifying extracellular gene functions, particularly in the tissue context. Here, we developed an approach for spatial functional genomics called Perturb-map. We applied Perturb-map to knock out dozens of genes in parallel in a mouse model of lung cancer and simultaneously assessed how each knockout influenced tumor growth, histopathology, and immune composition. Moreover, we paired Perturb-map and spatial transcriptomics for unbiased analysis of CRISPR-edited tumors. We found that in Tgfbr2 knockout tumors, the tumor microenvironment (TME) was converted to a fibro-mucinous state, and T cells excluded, concomitant with upregulated TGFß and TGFß-mediated fibroblast activation, indicating that TGFß-receptor loss on cancer cells increased TGFß bioavailability and its immunosuppressive effects on the TME. These studies establish Perturb-map for functional genomics within the tissue at single-cell resolution with spatial architecture preserved and provide insight into how TGFß responsiveness of cancer cells can affect the TME.


Assuntos
Neoplasias , Microambiente Tumoral , Animais , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas/genética , Genômica , Camundongos , Neoplasias/genética , Fator de Crescimento Transformador beta/genética
2.
Immunity ; 56(12): 2790-2802.e6, 2023 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-38091952

RESUMO

Neurodegenerative diseases (ND) are characterized by progressive loss of neuronal function. Mechanisms of ND pathogenesis are incompletely understood, hampering the development of effective therapies. Langerhans cell histiocytosis (LCH) is an inflammatory neoplastic disorder caused by hematopoietic progenitors expressing mitogen-activated protein kinase (MAPK)-activating mutations that differentiate into senescent myeloid cells that drive lesion formation. Some individuals with LCH subsequently develop progressive and incurable neurodegeneration (LCH-ND). Here, we showed that LCH-ND was caused by myeloid cells that were clonal with peripheral LCH cells. Circulating BRAFV600E+ myeloid cells caused the breakdown of the blood-brain barrier (BBB), enhancing migration into the brain parenchyma where they differentiated into senescent, inflammatory CD11a+ macrophages that accumulated in the brainstem and cerebellum. Blocking MAPK activity and senescence programs reduced peripheral inflammation, brain parenchymal infiltration, neuroinflammation, neuronal damage and improved neurological outcome in preclinical LCH-ND. MAPK activation and senescence programs in circulating myeloid cells represent targetable mechanisms of LCH-ND.


Assuntos
Histiocitose de Células de Langerhans , Proteínas Proto-Oncogênicas B-raf , Humanos , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Histiocitose de Células de Langerhans/genética , Histiocitose de Células de Langerhans/patologia , Histiocitose de Células de Langerhans/terapia , Encéfalo/metabolismo , Células Mieloides/metabolismo , Diferenciação Celular
3.
Nature ; 626(8001): 1108-1115, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38326622

RESUMO

Psychosocial stress has profound effects on the body, including the immune system and the brain1,2. Although a large number of pre-clinical and clinical studies have linked peripheral immune system alterations to stress-related disorders such as major depressive disorder (MDD)3, the underlying mechanisms are not well understood. Here we show that expression of a circulating myeloid cell-specific proteinase, matrix metalloproteinase 8 (MMP8), is increased in the serum of humans with MDD as well as in stress-susceptible mice following chronic social defeat stress (CSDS). In mice, we show that this increase leads to alterations in extracellular space and neurophysiological changes in the nucleus accumbens (NAc), as well as altered social behaviour. Using a combination of mass cytometry and single-cell RNA sequencing, we performed high-dimensional phenotyping of immune cells in circulation and in the brain and demonstrate that peripheral monocytes are strongly affected by stress. In stress-susceptible mice, both circulating monocytes and monocytes that traffic to the brain showed increased Mmp8 expression following chronic social defeat stress. We further demonstrate that circulating MMP8 directly infiltrates the NAc parenchyma and controls the ultrastructure of the extracellular space. Depleting MMP8 prevented stress-induced social avoidance behaviour and alterations in NAc neurophysiology and extracellular space. Collectively, these data establish a mechanism by which peripheral immune factors can affect central nervous system function and behaviour in the context of stress. Targeting specific peripheral immune cell-derived matrix metalloproteinases could constitute novel therapeutic targets for stress-related neuropsychiatric disorders.


Assuntos
Transtorno Depressivo Maior , Metaloproteinase 8 da Matriz , Monócitos , Estresse Psicológico , Animais , Humanos , Camundongos , Transtorno Depressivo Maior/sangue , Transtorno Depressivo Maior/enzimologia , Transtorno Depressivo Maior/genética , Transtorno Depressivo Maior/metabolismo , Espaço Extracelular/metabolismo , Metaloproteinase 8 da Matriz/sangue , Metaloproteinase 8 da Matriz/deficiência , Metaloproteinase 8 da Matriz/genética , Metaloproteinase 8 da Matriz/metabolismo , Camundongos Endogâmicos C57BL , Monócitos/química , Monócitos/imunologia , Monócitos/metabolismo , Núcleo Accumbens/metabolismo , Núcleo Accumbens/patologia , Tecido Parenquimatoso/metabolismo , Análise da Expressão Gênica de Célula Única , Comportamento Social , Isolamento Social , Estresse Psicológico/sangue , Estresse Psicológico/genética , Estresse Psicológico/imunologia , Estresse Psicológico/metabolismo
4.
Blood ; 135(18): 1548-1559, 2020 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-32181816

RESUMO

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.


Assuntos
Hematopoiese Clonal , Transplante de Células-Tronco Hematopoéticas/mortalidade , Células-Tronco Hematopoéticas/metabolismo , Doadores de Tecidos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Evolução Clonal/genética , Ensaio de Unidades Formadoras de Colônias , Análise Mutacional de DNA , Feminino , Células-Tronco Hematopoéticas/citologia , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Prognóstico , Telômero , Transplantados , Transplante Homólogo , Resultado do Tratamento , Adulto Jovem
5.
Curr Opin Hematol ; 28(2): 94-100, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33394723

RESUMO

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.


Assuntos
Hematopoiese Clonal , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Diferenciação Celular , Evolução Clonal/genética , Gerenciamento Clínico , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Avaliação de Resultados em Cuidados de Saúde , Prognóstico , Doadores de Tecidos , Transplante Autólogo , Transplante Homólogo
6.
Science ; 386(6720): eadn0327, 2024 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-39236155

RESUMO

Age is a major risk factor for cancer, but how aging impacts tumor control remains unclear. In this study, we establish that aging of the immune system, regardless of the age of the stroma and tumor, drives lung cancer progression. Hematopoietic aging enhances emergency myelopoiesis, resulting in the local accumulation of myeloid progenitor-like cells in lung tumors. These cells are a major source of interleukin (IL)-1⍺, which drives the enhanced myeloid response. The age-associated decline of DNA methyltransferase 3A enhances IL-1⍺ production, and disrupting IL-1 receptor 1 signaling early during tumor development normalized myelopoiesis and slowed the growth of lung, colonic, and pancreatic tumors. In human tumors, we identified an enrichment for IL-1⍺-expressing monocyte-derived macrophages linked to age, poorer survival, and recurrence, unraveling how aging promotes cancer and offering actionable therapeutic strategies.


Assuntos
Envelhecimento , DNA Metiltransferase 3A , Interleucina-1alfa , Neoplasias Pulmonares , Macrófagos , Mielopoese , Animais , Humanos , Camundongos , Envelhecimento/imunologia , DNA Metiltransferase 3A/deficiência , Hematopoese , Interleucina-1alfa/metabolismo , Interleucina-1alfa/genética , Interleucina-1beta/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Mielopoese/imunologia , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/imunologia , Transdução de Sinais
7.
bioRxiv ; 2023 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-37873371

RESUMO

Neurodegenerative diseases (ND) are characterized by progressive loss of neuronal function. Mechanisms of ND pathogenesis are incompletely understood, hampering the development of effective therapies. Langerhans cell histiocytosis (LCH) is an inflammatory neoplastic disorder caused by hematopoietic progenitors expressing MAPK activating mutations that differentiate into senescent myeloid cells that drive lesion formation. Some patients with LCH subsequently develop progressive and incurable neurodegeneration (LCH-ND). Here, we show that LCH-ND is caused by myeloid cells that are clonal with peripheral LCH cells. We discovered that circulating BRAF V600E + myeloid cells cause the breakdown of the blood-brain barrier (BBB), enhancing migration into the brain parenchyma where they differentiate into senescent, inflammatory CD11a + macrophages that accumulate in the brainstem and cerebellum. Blocking MAPK activity and senescence programs reduced parenchymal infiltration, neuroinflammation, neuronal damage and improved neurological outcome in preclinical LCH-ND. MAPK activation and senescence programs in circulating myeloid cells represent novel and targetable mechanisms of ND.

8.
Blood Adv ; 6(15): 4485-4489, 2022 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-35736667

RESUMO

Allogeneic hematopoietic stem cell transplantation (HSCT) offers a curative treatment approach for certain benign and malignant hematologic diseases. The actual HSCT is preceded by a conditioning therapy that reduces host-vs-HSCT graft rejection and creates niche space for transplanted hematopoietic stem and progenitor cells (HSPCs). Conditioning consists of chemotherapy with or without irradiation and is a major cause of side effects in HSCT. However, reduction of the intensity of cytotoxic conditioning leads to higher rates of engraftment failure and increased rates of relapse. We here tested if the addition of an HSC cycling inducing agent during conditioning allows to diminish the dose of conditioning drugs without reducing subsequent transplanted HSC engraftment in a mouse HSCT model. The thrombopoietin receptor agonist romiplostim was shown to induce cell cycling activity in hematopoietic stem cells (HSCs). We thus tested if the addition of romiplostim to the clinically applied conditioning chemotherapy regimen cyclophosphamide and busulfan leads to increased efficacy of the chemotherapeutic regimen. We found that romiplostim not only sensitizes HSCs to chemotherapy but also enables a reduction of the main chemotherapeutic component busulfan by half while HSC engraftment levels are maintained in long-term, serial transplantation assays.


Assuntos
Bussulfano , Transplante de Células-Tronco Hematopoéticas , Animais , Camundongos , Receptores Fc , Proteínas Recombinantes de Fusão , Trombopoetina/farmacologia , Trombopoetina/uso terapêutico , Condicionamento Pré-Transplante
9.
Cancer Immunol Res ; 10(11): 1354-1369, 2022 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-36095236

RESUMO

Tumor-associated macrophages (TAM) are one of the most abundant cell types in many solid tumors and typically exert protumor effects. This has led to an interest in macrophage-depleting agents for cancer therapy, but approaches developed to date have had limited success in clinical trials. Here, we report the development of a strategy for TAM depletion in mouse solid tumor models using chimeric antigen receptor (CAR) T cells targeting the macrophage marker F4/80 (F4.CAR-T). F4.CAR-T cells effectively killed macrophages in vitro and in vivo without toxicity. When injected into mice bearing orthotopic lung tumors, F4.CAR-T cells infiltrated tumor lesions and delayed tumor growth comparably with PD-1 blockade, and significantly extended mouse survival. Antitumor effects were mediated by F4.CAR-T-produced IFNγ, which promoted upregulation of MHC molecules on cancer cells and tumor-infiltrating myeloid cells. Notably, F4.CAR-T promoted expansion of endogenous CD8 T cells specific for tumor-associated antigen and led to immune editing of highly antigenic tumor cell clones. Antitumor impact was also observed in mouse models of ovarian and pancreatic cancer. These studies provide proof of principle to support CAR T-cell targeting of TAMs as a means to enhance antitumor immunity.


Assuntos
Receptores de Antígenos Quiméricos , Linfócitos T , Animais , Camundongos , Antígenos de Neoplasias , Linhagem Celular Tumoral , Modelos Animais de Doenças , Imunoterapia Adotiva , Macrófagos/metabolismo , Receptores de Antígenos Quiméricos/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Progressão da Doença
10.
Nat Med ; 27(5): 851-861, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33958797

RESUMO

Langerhans cell histiocytosis (LCH) is a potentially fatal condition characterized by granulomatous lesions with characteristic clonal mononuclear phagocytes (MNPs) harboring activating somatic mutations in mitogen-activated protein kinase (MAPK) pathway genes, most notably BRAFV600E. We recently discovered that the BRAFV600E mutation can also affect multipotent hematopoietic progenitor cells (HPCs) in multisystem LCH disease. How the BRAFV600E mutation in HPCs leads to LCH is not known. Here we show that enforced expression of the BRAFV600E mutation in early mouse and human multipotent HPCs induced a senescence program that led to HPC growth arrest, apoptosis resistance and a senescence-associated secretory phenotype (SASP). SASP, in turn, promoted HPC skewing toward the MNP lineage, leading to the accumulation of senescent MNPs in tissue and the formation of LCH lesions. Accordingly, elimination of senescent cells using INK-ATTAC transgenic mice, as well as pharmacologic blockade of SASP, improved LCH disease in mice. These results identify senescent cells as a new target for the treatment of LCH.


Assuntos
Senescência Celular/genética , Histiocitose de Células de Langerhans/genética , Histiocitose de Células de Langerhans/patologia , Células de Langerhans/patologia , Proteínas Proto-Oncogênicas B-raf/genética , Animais , Apoptose/genética , Proliferação de Células/genética , Senescência Celular/efeitos dos fármacos , Citocinas/metabolismo , Células-Tronco Hematopoéticas/patologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores
11.
Artigo em Inglês | MEDLINE | ID: mdl-33371225

RESUMO

The impact on health care of patients with myelodysplastic syndromes (MDS) is continuously rising. To investigate the perception of hemato-oncologists concerning the recommended MDS patient care in Switzerland, we conducted a web-based survey on diagnosis, risk-stratification and treatment. 43/309 physicians (13.9%) replied to 135 questions that were based on current guidelines between 3/2017 and 2/2018. Only questions with feedback-rates >50% were further analysed and ratios >90% defined "high agreement", 70-90% "agreement", 30-70% "insufficient agreement" and <30% "disagreement". For diagnosis, we found insufficient agreement on using flow-cytometry, classifying MDS precursor conditions, performing treatment response assessment after hypomethylating agents (HMA) and evaluating patients with suspected germ-line predisposition. For risk-stratification, we identified agreement on using IPSS-R but insufficient agreement for IPSS and patient-based assessments. For treatment, we observed disagreement on performing primary infectious prophylaxis in neutropenia but agreement on using only darbepoetin alfa in anaemic, lower-risk MDS patients. For thrombopoietin receptor agonists, insufficient agreement was found for the indication, preferred agent and triggering platelet count. Insufficient agreement was also found for immunosuppressive treatment in hypoplastic MDS and HMA dose adjustments. In conclusion, we identified areas for improvement in MDS patient care, in need of further clinical trials, information, and guiding documents.


Assuntos
Atenção à Saúde , Síndromes Mielodisplásicas/terapia , Adulto , Humanos , Imunossupressores , Síndromes Mielodisplásicas/tratamento farmacológico , Contagem de Plaquetas , Suíça
12.
Leukemia ; 34(10): 2688-2703, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32358567

RESUMO

Acute myeloid leukemia (AML) initiating and sustaining cells maintain high cell-surface similarity with their cells-of-origin, i.e., hematopoietic stem and progenitor cells (HSPCs), and identification of truly distinguishing leukemia-private antigens has remained elusive to date. To nonetheless utilize surface antigen-directed immunotherapy in AML, we here propose targeting both, healthy and malignant human HSPC, by chimeric antigen receptor (CAR) T-cells with specificity against CD117, the cognate receptor for stem cell factor. This approach should spare most mature hematopoietic cells and would require CAR T termination followed by subsequent transplantation of healthy HSPCs to rescue hematopoiesis. We successfully generated anti-CD117 CAR T-cells from healthy donors and AML patients. Anti-CD117 CAR T-cells efficiently targeted healthy and leukemic CD117-positive cells in vitro. In mice xenografted with healthy human hematopoiesis, they eliminated CD117-expressing, but not CD117-negative human cells. Importantly, in mice xenografted with primary human CD117-positive AML, they eradicated disease in a therapeutic setting. Administration of ATG in combination with rituximab, which binds to the co-expressed CAR T-cell transduction/selection marker RQR8, led to CAR T-cell depletion. Thus, we here provide the first proof of concept for the generation and preclinical efficacy of CAR T-cells directed against CD117-expressing human hematopoietic cells.


Assuntos
Imunoterapia Adotiva , Proteínas Proto-Oncogênicas c-kit/antagonistas & inibidores , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Animais , Biomarcadores , Biópsia , Medula Óssea/metabolismo , Medula Óssea/patologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Expressão Gênica , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/metabolismo , Neoplasias Hematológicas/terapia , Células-Tronco Hematopoéticas/imunologia , Células-Tronco Hematopoéticas/metabolismo , Humanos , Imunofenotipagem , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/imunologia , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/terapia , Depleção Linfocítica , Camundongos , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Proto-Oncogênicas c-kit/metabolismo , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos Quiméricos/genética , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Int J Antimicrob Agents ; 50(6): 726-729, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28797807

RESUMO

Recipients of allogeneic haematopoietic stem cell transplantation (allo-HSCT) are severely immunocompromised and are at increased risk of infection. In this prospective, observational, single-centre study including 110 allo-HSCT recipients, the rate of Staphylococcus aureus colonisation was reduced from 11.8% to 0% (P <0.001) following peritransplant oral gut decontamination. No invasive S. aureus infections were observed.


Assuntos
Descontaminação/métodos , Trato Gastrointestinal/microbiologia , Transplante de Células-Tronco Hematopoéticas , Boca/microbiologia , Infecções Estafilocócicas/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Hospedeiro Imunocomprometido , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Transplante Homólogo , Resultado do Tratamento , Adulto Jovem
14.
Cancer Epidemiol ; 46: 85-92, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28056392

RESUMO

Myelodysplastic syndromes (MDS) are emerging disorders of the elderly with an increasing burden on healthcare systems. He we report on the first population-based, epidemiological analysis of patients diagnosed with MDS in Switzerland between 2001 and 2012. The aim of this study was to characterize the extent and limitations of currently available population-based, epidemiological data and formulate recommendations for future health services research. The investigated outcomes comprised trends of annual case frequency, classification of morphological subtypes, incidence, mortality and survival. Annual case frequency increased by 20% (from 263 to 315 cases per year), whereas age-standardized incidence-/mortality-rates remained stable (2.5/1.1 per 100'000 person-years). This observation reflects population growth as well as higher diagnostic awareness and not an increase of age-specific risk. However, it will inevitably influence the future prevalence of MDS and the impact on healthcare systems. Reporting of classification in MDS subtypes was poor with modest improvement from 20% to 39% and increased awareness for mainly higher-risk diseases. Relative survival for all patients at 5-years (RS) ranged between 37 and 40%. Significant better RS was found for younger compared to older higher-risk MDS patients (48% vs. 17%), reflecting the effect of allogeneic hematopoietic stem-cell transplantation. However, no survival advantage was found in elderly patients after introduction of hypomethylating agents as standard for care in this patient group. Our data is in line with results from other MDS and cancer registries. It allows formulating recommendations for future collaborative health services research on MDS patients with national and international partners.


Assuntos
Síndromes Mielodisplásicas/classificação , Síndromes Mielodisplásicas/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Feminino , História do Século XXI , Humanos , Incidência , Masculino , Síndromes Mielodisplásicas/mortalidade , Sistema de Registros , Estudos Retrospectivos , Risco , Análise de Sobrevida , Suíça
16.
Nat Rev Immunol ; 20(6): 350, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32286536
18.
Exp Hematol ; 41(9): 823-831.e2, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23660069

RESUMO

Homing and engraftment of hematopoietic stem and progenitor cells (HSPCs) during bone marrow transplantation are critically dependent on integrins such as ß1-integrin. In the present study, we show that ß1-integrin and the tetraspanin CD63 form a cell surface receptor complex for the soluble serum protein tissue inhibitor of metalloproteinases-1 (TIMP-1) on human CD34⁺ HSPCs. Through binding to this receptor complex, TIMP-1 activates ß1-integrin, increases adhesion and migration of human CD34⁺ cells, and protects these cells from induced apoptosis. TIMP-1 stimulation in murine bone marrow mononuclear cells also promotes migration and adhesion; this is associated with augmented homing of murine mononuclear cells and of murine LSK⁺ cells during bone marrow transplantation. These results not only indicate that TIMP-1 is conducive to HSPC homing; they also identify CD63 and ß1-integrin as a TIMP-1 receptor complex on HSPCs.


Assuntos
Transplante de Medula Óssea , Movimento Celular , Sobrevivência de Enxerto , Células-Tronco Hematopoéticas/metabolismo , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Animais , Adesão Celular , Feminino , Humanos , Integrina beta1/metabolismo , Masculino , Camundongos , Tetraspanina 30/metabolismo , Transplante Homólogo
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