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Chai et al.1 reveal that the eukaryotic-like effector protein PtpB from Mycobacterium tuberculosis (MTB) dephosphorylates phospholipid membrane proteins, which prevents membrane localization of cleaved gasdermin D, inhibiting pyroptosis and cytokine release by infected macrophages to enable MTB immune evasion.
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Mycobacterium tuberculosis , Mycobacterium tuberculosis/metabolismo , Piroptosis , Ubiquitina/metabolismo , Macrófagos/metabolismo , Citocinas/metabolismoRESUMEN
Cells acquire their fate in vivo in the context of a complex microenvironmental "niche" comprised of heterologous cell types, signaling molecules, extracellular matrix, biophysical forces, and metabolic substrates. Now Calderón and Boehm report the "refunctionalization" of a defective thymic epithelial niche, offering insights into how signaling molecules may be hierarchically organized to direct differentiation outcomes.
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Ex vivo expansion of human CD34+ hematopoietic stem and progenitor cells remains a challenge due to rapid differentiation after detachment from the bone marrow niche. In this study, we assessed the capacity of an inducible fusion protein to enable sustained ex vivo proliferation of hematopoietic precursors and their capacity to differentiate into functional phagocytes. We fused the coding sequences of an FK506-Binding Protein 12 (FKBP12)-derived destabilization domain (DD) to the myeloid/lymphoid lineage leukemia/eleven nineteen leukemia (MLL-ENL) fusion gene to generate the fusion protein DD-MLL-ENL and retrovirally expressed the protein switch in human CD34+ progenitors. Using Shield1, a chemical inhibitor of DD fusion protein degradation, we established large-scale and long-term expansion of late monocytic precursors. Upon Shield1 removal, the cells lost self-renewal capacity and spontaneously differentiated, even after 2.5 y of continuous ex vivo expansion. In the absence of Shield1, stimulation with IFN-γ, LPS, and GM-CSF triggered terminal differentiation. Gene expression analysis of the obtained phagocytes revealed marked similarity with naïve monocytes. In functional assays, the novel phagocytes migrated toward CCL2, attached to VCAM-1 under shear stress, produced reactive oxygen species, and engulfed bacterial particles, cellular particles, and apoptotic cells. Finally, we demonstrated Fcγ receptor recognition and phagocytosis of opsonized lymphoma cells in an antibody-dependent manner. Overall, we have established an engineered protein that, as a single factor, is useful for large-scale ex vivo production of human phagocytes. Such adjustable proteins have the potential to be applied as molecular tools to produce functional immune cells for experimental cell-based approaches.
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Diferenciación Celular , Fagocitos , Humanos , Fagocitos/metabolismo , Células Madre Hematopoyéticas/metabolismo , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismo , Proteínas Recombinantes de Fusión/metabolismo , Proteínas Recombinantes de Fusión/genética , Proteína de la Leucemia Mieloide-Linfoide/metabolismo , Proteína de la Leucemia Mieloide-Linfoide/genética , Leucemia/genética , Leucemia/patología , Leucemia/metabolismo , Ingeniería de Proteínas/métodos , FagocitosisRESUMEN
B-cell acute lymphoblastic leukemia (B-ALL) occurs most commonly in children, whereas chronic myeloid leukemia is more frequent in adults. The myeloid bias of hematopoiesis in elderly individuals has been considered causative, but the age of the bone marrow microenvironment (BMM) may be contributory. Using various murine models of B-ALL in young vs old mice, we recapitulated B-ALL preponderance in children vs adults. We showed differential effects of young vs old BM macrophages on B-ALL cell function. Molecular profiling using RNA- and ATAC-sequencing revealed pronounced differences in young vs old BMM-derived macrophages and enrichment for gene sets associated with inflammation. In concordance with the role of C-X-C motif chemokine (CXCL) 13 for disease-associated B-cell chemoattraction, we found CXCL13 to be highly expressed in young macrophages on a translational compared with a transcriptional level. Inhibition of CXCL13 in BM macrophages impaired leukemia cell migration and decreased the proliferation of cocultured B-ALL cells, whereas recombinant CXCL13 increased pAKT and B-ALL cell expansion. Pretreatment of B-ALL-initiating cells with CXCL13 accelerated B-ALL progression. Deficiency of Cxcr5, the receptor for CXCL13, on B-ALL-initiating cells prolonged murine survival, whereas high expression of CXCR5 in pediatric B-ALL may predict central nervous system relapse. CXCL13 staining was increased in bone sections from pediatric compared with adult patients with B-ALL. Taken together, our study shows that the age of the BMM and, in particular, BM macrophages influence the leukemia phenotype. The CXCR5-CXCL13 axis may act as prognostic marker and an attractive novel target for the treatment of B-ALL.
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Quimiocina CXCL13/genética , Regulación Leucémica de la Expresión Génica , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Receptores CXCR5/genética , Microambiente Tumoral , Envejecimiento , Animales , Médula Ósea/metabolismo , Médula Ósea/patología , Línea Celular Tumoral , Progresión de la Enfermedad , Humanos , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologíaRESUMEN
Vitamin K antagonists (VKAs) have been used in 1% of the world's population for prophylaxis or treatment of thromboembolic events for 64 years. Impairment of osteoblast function and osteoporosis has been described in patients receiving VKAs. Given the involvement of cells of the bone marrow microenvironment (BMM), such as mesenchymal stem cells (MSCs) and macrophages, as well as other factors such as the extracellular matrix for the maintenance of normal hematopoietic stem cells (HSCs), we investigated a possible effect of VKAs on hematopoiesis via the BMM. Using various transplantation and in vitro assays, we show here that VKAs alter parameters of bone physiology and reduce functional HSCs 8-fold. We implicate impairment of the functional, secreted, vitamin K-dependent, γ-carboxylated form of periostin by macrophages and, to a lesser extent, MSCs of the BMM and integrin ß3-AKT signaling in HSCs as at least partly causative of this effect, with VKAs not being directly toxic to HSCs. In patients, VKA use associates with modestly reduced leukocyte and monocyte counts, albeit within the normal reference range. VKAs decrease human HSC engraftment in immunosuppressed mice. Following published examples that alteration of the BMM can lead to hematological malignancies in mice, we describe, without providing a causal link, that the odds of VKA use are higher in patients with vs without a diagnosis of myelodysplastic syndrome (MDS). These results demonstrate that VKA treatment impairs HSC function via impairment of the BMM and the periostin/integrin ß3 axis, possibly associating with increased MDS risk.
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Células de la Médula Ósea/efectos de los fármacos , Células de la Médula Ósea/metabolismo , Microambiente Celular/efectos de los fármacos , Hematopoyesis/efectos de los fármacos , Vitamina K/antagonistas & inhibidores , Animales , Anticoagulantes/farmacología , Biomarcadores , Moléculas de Adhesión Celular/metabolismo , Relación Dosis-Respuesta a Droga , Células Madre Hematopoyéticas/efectos de los fármacos , Células Madre Hematopoyéticas/metabolismo , Leucocitos/inmunología , Leucocitos/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Macrófagos/metabolismo , Ratones , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/etiología , Síndromes Mielodisplásicos/metabolismo , Vitamina K/farmacología , Warfarina/farmacologíaRESUMEN
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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Células de la Médula Ósea/citología , Médula Ósea/crecimiento & desarrollo , Células Madre Hematopoyéticas , Microambiente Tumoral/genética , Médula Ósea/patología , Hematopoyesis , Humanos , Leucemia/genética , Leucemia/patología , Nicho de Células Madre/genéticaRESUMEN
The endosteal bone marrow niche and vascular endothelial cells provide sanctuaries for leukemic cells. In murine chronic myeloid leukemia (CML) CD44 on leukemia cells and E-selectin on bone marrow endothelium are essential mediators for the engraftment of leukemic stem cells. We hypothesized that non-adhesion of CML-initiating cells to E-selectin on the bone marrow endothelium may lead to superior eradication of leukemic stem cells in CML after treatment with imatinib than imatinib alone. Indeed, here we show that treatment with the E-selectin inhibitor GMI-1271 in combination with imatinib prolongs survival of mice with CML via decreased contact time of leukemia cells with bone marrow endothelium. Non-adhesion of BCR-ABL1+ cells leads to an increase of cell cycle progression and an increase of expression of the hematopoietic transcription factor and proto-oncogene Scl/Tal1 in leukemia-initiating cells. We implicate SCL/TAL1 as an indirect phosphorylation target of BCR-ABL1 and as a negative transcriptional regulator of CD44 expression. We show that increased SCL/TAL1 expression is associated with improved outcome in human CML. These data demonstrate the BCR-ABL1-specific, cell-intrinsic pathways leading to altered interactions with the vascular niche via the modulation of adhesion molecules - which could be exploited therapeutically in the future.
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Proteínas de Fusión bcr-abl , Leucemia Mielógena Crónica BCR-ABL Positiva , Animales , Médula Ósea , Selectina E/genética , Células Endoteliales , Proteínas de Fusión bcr-abl/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Ratones , Proto-Oncogenes Mas , Proteína 1 de la Leucemia Linfocítica T AgudaRESUMEN
In this review article, we present recent updates on the hematologic tumor microenvironment following the 3rd Scientific Workshop on the Haematological Tumour Microenvironment and its Therapeutic Targeting organized by the European School of Hematology, which took place at the Francis Crick Institute in London in February 2019. This review article is focused on recent scientific advances highlighted in the invited presentations at the meeting, which encompassed the normal and malignant niches supporting hematopoietic stem cells and their progeny. Given the precise focus, it does not discuss other relevant contributions in this field, which have been the scope of other recent reviews. The content covers basic research and possible clinical applications with the major therapeutic angle of utilizing basic knowledge to devise new strategies to target the tumor microenvironment in hematologic cancers. The review is structured in the following sections: (i) regulation of normal hematopoietic stem cell niches during development, adulthood and aging; (ii) metabolic adaptation and reprogramming in the tumor microenvironment; (iii) the key role of inflammation in reshaping the normal microenvironment and driving hematopoietic stem cell proliferation; (iv) current understanding of the tumor microenvironment in different malignancies, such as chronic lymphocytic leukemia, multiple myeloma, acute myeloid leukemia and myelodysplastic syndromes; and (v) the effects of therapies on the microenvironment and some opportunities to target the niche directly in order to improve current treatments.
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Neoplasias Hematológicas/metabolismo , Hematopoyesis , Células Madre Hematopoyéticas/metabolismo , Microambiente Tumoral , Neoplasias Hematológicas/patología , Neoplasias Hematológicas/terapia , Células Madre Hematopoyéticas/patología , HumanosRESUMEN
Recent strategies for treating CML patients have focused on investigating new combinations of tyrosine kinase inhibitors (TKIs) as well as identifying novel translational research agents that can eradicate CML leukemia-initiating cells (CML-LICs). However, little is known about the therapeutic benefits such CML-LIC targeting therapies might bring to CML patients. In this study, we investigated the therapeutic potential of EW-7197, an orally bioavailable transforming growth factor-ß signaling inhibitor which has recently been approved as an Investigational New Drug (NIH, USA), to suppress CML-LICs in vivo. Compared to TKI treatment alone, administration of TKI plus EW-7197 to CML-affected mice significantly delayed disease relapse and prolonged survival. Notably, combined treatment with EW-7197 plus TKI was effective in eliminating CML-LICs even if they expressed the TKI-resistant T315I mutant BCR-ABL1 oncogene. Collectively, these results indicate that EW-7197 may be a promising candidate for a new therapeutic that can greatly benefit CML patients by working in combination with TKIs to eradicate CML-LICs.
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Compuestos de Anilina/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Triazoles/farmacología , Animales , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Humanos , Imidazoles/administración & dosificación , Ratones , Ratones Endogámicos C57BL , Inhibidores de Proteínas Quinasas/administración & dosificación , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Piridazinas/administración & dosificación , Receptor Tipo I de Factor de Crecimiento Transformador beta , Receptores de Factores de Crecimiento Transformadores beta/antagonistas & inhibidores , Transfección , Factor de Crecimiento Transformador beta/antagonistas & inhibidoresRESUMEN
We investigated adhesion pathways that contribute to engraftment of breakpoint cluster region-Abelson murine leukemia viral oncogene homolog 1 (BCR-ABL1)-induced chronic myelogenous leukemia (CML)-like myeloproliferative neoplasia in a mouse retroviral transduction/transplantation model. Compared with normal stem/progenitor cells, BCR-ABL1(+) progenitors had similar expression of very late antigen-4 (VLA4), VLA5, leukocyte functional antigen-1, and CXCR4 but lower expression of P-selectin glycoprotein ligand-1 (PSGL-1) and of L-selectin. Whereas vascular cell adhesion molecule-1 and P-selectin were not required, deficiency of E-selectin in the recipient bone marrow endothelium significantly reduced engraftment by BCR-ABL1-expressing stem cells following intravenous injection, with leukemogenesis restored by direct intrafemoral injection. BCR-ABL1-expressing cells deficient for PSGL-1 or the selectin ligand-synthesizing enzymes core-2 ß1,6-N-acetylglucosaminyltransferase or fucosyltransferases IV/VII were impaired for engraftment, and destruction of selectin ligands on leukemic progenitors by neuraminidase reduced engraftment. BCR-ABL1-expressing L-selectin-deficient progenitors were also defective in homing and engraftment, with leukemogenesis rescued by coexpression of chimeric E/L-selectin. Antibody to L-selectin decreased the engraftment of BCR-ABL1-transduced stem cells. These results establish that BCR-ABL1(+) leukemic stem cells rely to a greater extent on selectins and their ligands for homing and engraftment than do normal stem cells. Selectin blockade is a novel strategy to exploit differences between normal and leukemic stem cells that may be beneficial in autologous transplantation for CML and perhaps other leukemias.
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Médula Ósea/patología , Movimiento Celular/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Células Madre Neoplásicas/fisiología , Selectinas/fisiología , Nicho de Células Madre , Animales , Células de la Médula Ósea/patología , Células Cultivadas , Proteínas de Fusión bcr-abl/genética , Proteínas de Fusión bcr-abl/metabolismo , Células HEK293 , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Ligandos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Invasividad Neoplásica , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patologíaRESUMEN
Cancer therapy has progressed remarkably in recent years. In no area has this been more apparent than in the development of "targeted therapies", particularly those using drugs that inhibit the activity of certain tyrosine kinases, activating mutations or amplifications of which are causal, or strongly contributory, to tumorigenesis. However, some of these therapies have been associated with toxicity to the heart. Here we summarize what is known about the cardiotoxicity of cancer drugs that target tyrosine kinases. We focus on basic mechanisms through which interruption of specific signalling pathways leads to cardiomyocyte dysfunction and/or death, and contrast this with therapeutic responses in cancer cells.
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Cardiopatías/inducido químicamente , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/efectos adversos , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Adaptadoras Transductoras de Señales/antagonistas & inhibidores , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados , Bencenosulfonatos/efectos adversos , Sistemas de Liberación de Medicamentos , Inhibidores Enzimáticos/efectos adversos , Corazón/crecimiento & desarrollo , Corazón/fisiología , Humanos , Indoles/efectos adversos , Lapatinib , Modelos Biológicos , Niacinamida/análogos & derivados , Compuestos de Fenilurea , Proteínas Proto-Oncogénicas c-abl/antagonistas & inhibidores , Piridinas/efectos adversos , Pirroles/efectos adversos , Quinazolinas/efectos adversos , Sorafenib , Sunitinib , TrastuzumabRESUMEN
Neutrophils are phagocytic cells that play a critical role in innate immunity by destroying bacterial pathogens. Channels belonging to the inward rectifier potassium channel subfamily 2 (Kir2 channels) have been described in other phagocytes (monocytes/macrophages and eosinophils) and in hematopoietic precursors of phagocytes. Their physiological function in these cells remains unclear, but some evidence suggests a role in growth factor-dependent proliferation and development. Expression of functional Kir2 channels has not been definitively demonstrated in mammalian neutrophils. Here, we show by RT-PCR that neutrophils from mouse bone marrow and liver express mRNA for the Kir2 subunit Kir2.1 but not for other subunits (Kir2.2, Kir2.3, and Kir2.4). In electrophysiological experiments, resting (unstimulated) neutrophils from mouse bone marrow and liver exhibit a constitutively active, external K(+)-dependent, strong inwardly rectifying current that constitutes the dominant current. The reversal potential is dependent on the external K(+) concentration in a Nernstian fashion, as expected for a K(+)-selective current. The current is not altered by changes in external or internal pH, and it is blocked by Ba(2+), Cs(+), and the Kir2-selective inhibitor ML133. The single-channel conductance is in agreement with previously reported values for Kir2.1 channels. These properties are characteristic of homomeric Kir2.1 channels. Current density in short-term cultures of bone marrow neutrophils is decreased in the absence of growth factors that are important for neutrophil proliferation [granulocyte colony-stimulating factor (G-CSF) and stem cell factor (SCF)]. These results demonstrate that mouse neutrophils express functional Kir2.1 channels and suggest that these channels may be important for neutrophil function, possibly in a growth factor-dependent manner.
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Médula Ósea/metabolismo , Hígado/metabolismo , Neutrófilos/metabolismo , Canales de Potasio de Rectificación Interna/biosíntesis , Animales , Células Cultivadas , Femenino , Regulación de la Expresión Génica , Hígado/citología , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
Hematopoietic progenitors are regulated in their respective niches by cells of the bone marrow microenvironment. The bone marrow microenvironment is composed of a variety of cell types, and the relative contribution of each of these cells for hematopoietic lineage maintenance has remained largely unclear. Osteocytes, the most abundant yet least understood cells in bone, are thought to initiate adaptive bone remodeling responses via osteoblasts and osteoclasts. Here we report that these cells regulate hematopoiesis, constraining myelopoiesis through a Gsα-mediated mechanism that affects G-CSF production. Mice lacking Gsα in osteocytes showed a dramatic increase in myeloid cells in bone marrow, spleen, and peripheral blood. This hematopoietic phenomenon was neither intrinsic to the hematopoietic cells nor dependent on osteoblasts but was a consequence of an altered bone marrow microenvironment imposed by Gsα deficiency in osteocytes. Conditioned media from osteocyte-enriched bone explants significantly increased myeloid colony formation in vitro, which was blocked by G-CSFneutralizing antibody, indicating a critical role of osteocyte-derived G-CSF in the myeloid expansion.
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Subunidades alfa de la Proteína de Unión al GTP Gs/metabolismo , Mielopoyesis , Osteocitos/metabolismo , Transducción de Señal , Proteínas Adaptadoras Transductoras de Señales , Animales , Enfermedades Óseas Metabólicas/genética , Enfermedades Óseas Metabólicas/metabolismo , Células de la Médula Ósea/metabolismo , Proliferación Celular , Células Cultivadas , Microambiente Celular/genética , Femenino , Subunidades alfa de la Proteína de Unión al GTP Gs/genética , Expresión Génica , Glicoproteínas/genética , Glicoproteínas/metabolismo , Factor Estimulante de Colonias de Granulocitos/genética , Factor Estimulante de Colonias de Granulocitos/metabolismo , Inmunohistoquímica , Péptidos y Proteínas de Señalización Intercelular , Masculino , Ratones , Ratones Noqueados , Microscopía Electrónica de Rastreo , Células Mieloides/metabolismo , Osteocitos/citología , Osteocitos/ultraestructura , Receptor de Hormona Paratiroídea Tipo 1/genética , Receptor de Hormona Paratiroídea Tipo 1/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Bazo/citología , Bazo/metabolismoRESUMEN
Our understanding of the biology of the normal hematopoietic stem cell niche has increased steadily due to improved murine models and sophisticated imaging tools. Less well understood, but of growing interest, is the interaction between cells in the bone marrow during the initiation, maintenance and treatment of hematologic neoplasms. This review summarizes the emerging concepts of the normal and leukemic hematopoietic bone marrow niche. Furthermore, it reviews current models of how the microenvironment of the bone marrow may contribute to or be modified by leukemogenesis. Finally, it provides the rationale for a "two-pronged" approach, directly targeting cancer cells themselves while also targeting the bone microenvironment to make it inhospitable to malignant cells and, ultimately, eradicating cancer stem-like cells.
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Médula Ósea/metabolismo , Neoplasias Hematológicas/metabolismo , Células Madre Hematopoyéticas/metabolismo , Nicho de Células Madre , Microambiente Tumoral , Animales , Médula Ósea/patología , Neoplasias Hematológicas/patología , Neoplasias Hematológicas/terapia , Células Madre Hematopoyéticas/patología , HumanosRESUMEN
Cancer-associated thrombosis often lacks a clear etiology. However, it is linked to a poor prognosis and represents the second-leading cause of death in cancer patients. Recent studies have shown that chromatin released into blood, through the generation of neutrophil extracellular traps (NETs), is procoagulant and prothrombotic. Using a murine model of chronic myelogenous leukemia, we show that malignant and nonmalignant neutrophils are more prone to NET formation. This increased sensitivity toward NET generation is also observed in mammary and lung carcinoma models, suggesting that cancers, through a systemic effect on the host, can induce an increase in peripheral blood neutrophils, which are predisposed to NET formation. In addition, in the late stages of the breast carcinoma model, NETosis occurs concomitant with the appearance of venous thrombi in the lung. Moreover, simulation of a minor systemic infection in tumor-bearing, but not control, mice results in the release of large quantities of chromatin and a prothrombotic state. The increase in neutrophil count and their priming is mediated by granulocyte colony-stimulating factor (G-CSF), which accumulates in the blood of tumor-bearing mice. The prothrombotic state in cancer can be reproduced by treating mice with G-CSF combined with low-dose LPS and leads to thrombocytopenia and microthrombosis. Taken together, our results identify extracellular chromatin released through NET formation as a cause for cancer-associated thrombosis and unveil a target in the effort to decrease the incidence of thrombosis in cancer patients.
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Cromatina/metabolismo , Leucemia Mielógena Crónica BCR-ABL Positiva/complicaciones , Neutrófilos/metabolismo , Trombosis/etiología , Animales , Western Blotting , Cromatina/inmunología , ADN/sangre , Ensayo de Inmunoadsorción Enzimática , Fluorescencia , Factor Estimulante de Colonias de Granulocitos/sangre , Técnicas Histológicas , Ratones , Ratones Endogámicos BALB C , Neutrófilos/inmunología , Estadísticas no Paramétricas , Trombosis/prevención & controlRESUMEN
Inflammation promotes solid tumor progression, but how regulatory mechanisms of inflammation may impact leukemia is less well studied. Using annexin A5 (ANXA 5), a calcium-binding protein known for apoptosis, which we discovered to be differentially expressed in the bone marrow microenvironment (BMM) of mice with acute myeloid (AML) versus chronic myeloid leukemia, as a model system, we unravel here a circuit in which AML-derived tumor necrosis factor (TNF)α dose-dependently reduces ANXA5 in the BMM. This creates an inflammatory BMM via elevated levels of prostaglandin E2 (PGE2). Via binding to its EP4 receptor, PGE2 increases ï¢-catenin and hypoxia-inducible factor (HIF) 1 α signaling in AML cells, thereby accelerating PGE2-sensitive AML. Human trephine biopsies may show lower ANXA5 expression and higher PGE2 expression in AML compared to other hematological malignancies. Further, syngeneic and xenogeneic transplantation models suggest a survival benefit after treatment with the inhibitor of prostaglandin-endoperoxide synthase 2 (cyclooxygenase 2 (COX2)), celecoxib, plus cytarabine in those AML types highly sensitive to PGE2 compared to cytarabine alone. Taken together, TNFα/ANXA5/NF-kB/COX2/PGE2-mediated inflammation influences AML course in a highly differential and circular manner, and AML patients with 'inflammatory AML' may benefit from antiphlogistic agents as adjunct therapy.