Showing papers on "Myeloid published in 2003"
TL;DR: It is found that activation of HIF-1alpha is essential for myeloid cell infiltration and activation in vivo through a mechanism independent of VEGF, and its direct regulation of survival and function in the inflammatory microenvironment is demonstrated.
1,773 citations
TL;DR: It is shown that a fraction of blood monocyte-derived myeloid dendritic cells (MDCs) express B7-H1, a member of the B7 family, on the cell surface, which could be further upregulated by tumor environmental factors.
Abstract: Suppression of dendritic cell function in cancer patients is thought to contribute to the inhibi- tion of immune responses and disease progression. Molecular mechanisms of this suppression remain elusive, however. Here, we show that a fraction of blood monocyte-derived myeloid dendritic cells (MDCs) express B7-H1, a member of the B7 family, on the cell surface. B7-H1 could be further upregulated by tumor environmental factors. Consistent with this finding, vir- tually all MDCs isolated from the tissues or draining lymph nodes of ovarian carcinomas ex- press B7-H1. Blockade of B7-H1 enhanced MDC-mediated T-cell activation and was accompanied by downregulation of T-cell interleukin (IL)-10 and upregulation of IL-2 and in- terferon (IFN)-γ. T cells conditioned with the B7-H1-blocked MDCs had a more potent ability to inhibit autologous human ovarian carcinoma growth in non-obese diabetic-severe combined immunodeficient (NOD-SCID) mice. Therefore, upregulation of B7-H1 on MDCs in the tumor microenvironment downregulates T-cell immunity. Blockade of B7-H1 represents one ap- proach for cancer immunotherapy.
1,240 citations
TL;DR: The ability of transient repopulating progenitors to initiate myeloid leukemias in response to an MLL oncogene is unequivocally established, and the existence of cancer stem cells that do not necessarily overlap with multipotent stem cells of the tissue of origin is supported.
Abstract: We have used the hematopoietic system as a model to investigate whether acute myeloid leukemia arises exclusively from self-renewing stem cells or also from short-lived myeloid progenitors. When transduced with a leukemogenic MLL fusion gene, prospectively isolated stem cells and myeloid progenitor populations with granulocyte/macrophage differentiation potential are efficiently immortalized in vitro and result in the rapid onset of acute myeloid leukemia with similar latencies following transplantation in vivo. Regardless of initiating cell, leukemias displayed immunophenotypes and gene expression profiles characteristic of maturation arrest at an identical late stage of myelomonocytic differentiation, putatively a monopotent monocytic progenitor stage. Our findings unequivocally establish the ability of transient repopulating progenitors to initiate myeloid leukemias in response to an MLL oncogene, and support the existence of cancer stem cells that do not necessarily overlap with multipotent stem cells of the tissue of origin.
685 citations
TL;DR: It is shown that common lymphoid and common myeloid progenitors, as well as steady state DCs in thymus, spleen, and epidermis, express Flt3, and it is demonstrated that FlT3L can drive DC development along both the lymphoids and myeloids developmental pathways from Flt 3+ progenitor cells and their progeny DCs.
Abstract: Stimulation of Flt3 receptor tyrosine kinase through its cognate ligand expands early hematopoietic progenitor and dendritic cells (DCs) in humans and mice. The exact developmental stages at which hematopoietic progenitors express Flt3, are responsive to its ligand, and subsequently develop to DCs, are not known. Here we show that common lymphoid and common myeloid progenitors, as well as steady state DCs in thymus, spleen, and epidermis, express Flt3. The receptor is down-regulated once definitive B cell, T cell, and megakaryocyte/erythrocyte commitment occurs, and Flt3 is not detectable on other steady state hematopoietic cell populations. Upon in vivo Flt3 ligand (Flt3L) administration, Flt3+ progenitor cells and their progeny DCs are expanded, whereas Flt3− downstream progenitors are not, or are only slightly increased. Transplantation of common lymphoid and common myeloid progenitors and subsequent Flt3L injection increases progeny DCs of both precursor populations. These findings provide a definitive map of Flt3 expression in the hematopoietic hierarchy and directly demonstrate that Flt3L can drive DC development along both the lymphoid and myeloid developmental pathways from Flt3+ progenitors to Flt3+ DCs.
578 citations
TL;DR: NOS2 and Arg1 might act separately or synergistically in vivo to control specific types of T-cell responses, and selective antagonists of these enzymes might prove beneficial in fighting diseases in which T- cell responses are inappropriately suppressed.
577 citations
28 Nov 2003
TL;DR: The available evidence indicates that activating mutations in the hematopoietic tyrosine kinases FLT3 and c-KIT, and in N-Ras and K-RAS, confer proliferative advantage to hematocompetence progenitors and cooperate with loss-of-function mutations in hematOPOietic transcription factors to cause an acute leukemia phenotype characterized by proliferation and impaired differentiation.
Abstract: ▪ Abstract Human leukemias are typified by acquired recurring chromosomal translocations. Cloning of these translocation breakpoints has provided important insights into pathogenesis of disease as well as novel therapeutic approaches. Chronic myelogenous leukemias (CML) are caused by constitutively activated tyrosine kinases, such as BCR/ABL, that confer a proliferative and survival advantage to hematopoietic progenitors but do not affect differentiation. These activated kinases are validated targets for therapy with selective tyrosine kinase inhibitors, a paradigm that may have broad applications in treatment of hematologic malignancies as well as solid tumors. Chromosomal translocations in acute myeloid leukemias (AML) most often result in loss-of-function mutations in transcription factors that are required for normal hematopoietic development. These latter mutations, however, are not sufficient to cause AML. The available evidence indicates that activating mutations in the hematopoietic tyrosine kinas...
561 citations
TL;DR: Results indicate that inhibition of BCR/ABL tyrosine kinase activity by imatinib mesylate does not eliminate malignant primitive progenitors in CML patients.
551 citations
TL;DR: It is found that VLA-4-positive cells acquired resistance to anoikis (loss of anchorage) or drug-induced apoptosis through the phosphatidylinositol-3-kinase (PI-3K)/AKT/Bcl-2 signaling pathway, which is activated by the interaction of V LA-4 and fibronectin.
Abstract: Bone-marrow minimal residual disease (MRD) causes relapse after chemotherapy in patients with acute myelogenous leukemia (AML). We postulate that the drug resistance is induced by the attachment of very late antigen (VLA)-4 on leukemic cells to fibronectin on bone-marrow stromal cells. We found that VLA-4-positive cells acquired resistance to anoikis (loss of anchorage) or drug-induced apoptosis through the phosphatidylinositol-3-kinase (PI-3K)/AKT/Bcl-2 signaling pathway, which is activated by the interaction of VLA-4 and fibronectin. This resistance was negated by VLA-4-specific antibodies. In a mouse model of MRD, we achieved a 100% survival rate by combining VLA-4-specific antibodies and cytosine arabinoside (AraC), whereas AraC alone prolonged survival only slightly. In addition, overall survival at 5 years was 100% for 10 VLA-4-negative patients and 44.4% for 15 VLA-4-positive patients. Thus, the interaction between VLA-4 on leukemic cells and fibronectin on stromal cells may be crucial in bone marrow MRD and AML prognosis.
528 citations
TL;DR: It is shown that Arg1 increases superoxide production in myeloid cells through a pathway that likely utilizes the reductase domain of inducible NO synthase (iNOS), and that superoxide is required for Arg1-dependent suppression of T cell function.
Abstract: We previously demonstrated that a specialized subset of immature myeloid cells migrate to lymphoid organs as a result of tumor growth or immune stress, where they suppress B and T cell responses to Ags. Although NO was required for suppression of mitogen activation of T cells by myeloid suppressor cells (MSC), it was not required for suppression of allogenic responses. In this study, we describe a novel mechanism used by MSC to block T cell proliferation and CTL generation in response to alloantigen, which is mediated by the enzyme arginase 1 (Arg1). We show that Arg1 increases superoxide production in myeloid cells through a pathway that likely utilizes the reductase domain of inducible NO synthase (iNOS), and that superoxide is required for Arg1-dependent suppression of T cell function. Arg1 is induced by IL-4 in freshly isolated MSC or cloned MSC lines, and is therefore up-regulated by activated Th2, but not Th1, cells. In contrast, iNOS is induced by IFN-gamma and Th1 cells. Because Arg1 and iNOS share L-arginine as a common substrate, our results indicate that L-arginine metabolism in myeloid cells is a potential target for selective intervention in reversing myeloid-induced dysfunction in tumor-bearing hosts.
498 citations
TL;DR: It is demonstrated here that primary myeloid progenitors immortalized by various MLL oncoproteins exhibit a characteristic Hoxa gene cluster expression profile, which reflects that preferentially expressed in the myeloids clonogenic progenitor fraction of normal bone marrow.
Abstract: Transcriptional deregulation through the production of dominant-acting chimeric transcription factors derived from chromosomal translocations is a common theme in the pathogenesis of acute leukemias; however, the essential target genes for acute leukemogenesis are unknown. We demonstrate here that primary myeloid progenitors immortalized by various MLL oncoproteins exhibit a characteristic Hoxa gene cluster expression profile, which reflects that preferentially expressed in the myeloid clonogenic progenitor fraction of normal bone marrow. Continued maintenance of this MLL-dependent Hoxa gene expression profile is associated with conditional MLL-associated myeloid immortalization. Moreover, Hoxa7 and Hoxa9 were specifically required for efficient in vitro myeloid immortalization by an MLL fusion protein but not other leukemogenic fusion proteins. Finally, in a bone marrow transduction/transplantation model, Hoxa9 is essential for MLL-dependent leukemogenesis in vivo, a primary requirement detected at the earliest stages of disease initiation. Thus, a genetic reliance on Hoxa7 and Hoxa9 in MLL-mediated transformation demonstrates a gain-of-function mechanism for MLL oncoproteins as upstream constitutive activators that promote myeloid transformation via a Hox-dependent mechanism.
459 citations
TL;DR: It is demonstrated that the early precursors for all DC subtypes are within the BM Flt3+ precursor populations, regardless of their lymphoid or myeloid lineage orientation.
Abstract: Flt3 ligand (Flt3L) is a growth factor for hemopoietic progenitors and can promote the expansion of both conventional dendritic cells (DCs) and plasmacytoid predendritic cells (p-preDCs). The cells responding to Flt3L treatment and the precursors for the DCs and p-preDCs had not been fully characterized. We examined different mouse bone marrow (BM) hemopoietic precursor populations for the surface expression of Flt3 and tested them for early DC and p-preDC precursor activity. Most DC precursor activity, other than that given by multipotent hemopoietic stem cells, was within the downstream precursors expressing Flt3. The majority of mouse BM common lymphoid precursors expressed high levels of Flt3 and these were the most efficient precursors of both DCs and p-preDCs. In contrast, only a small proportion of the common myeloid precursors (CMPs) expressed Flt3, but the precursor activity for both DCs and p-preDCs was within this minor Flt3+ CMP fraction. The granulocyte and macrophage precursors and pro-B cells did not express Flt3 and had no DC or p-preDC precursor activity. These findings demonstrate that the early precursors for all DC subtypes are within the BM Flt3+ precursor populations, regardless of their lymphoid or myeloid lineage orientation.
TL;DR: The results indicate that circulating myeloid cells, in response to inflammatory cues, migrate to regenerating skeletal muscle and stochastically incorporate into mature myofibers.
Abstract: Recent studies have shown that cells from the bone marrow can give rise to differentiated skeletal muscle fibers. However, the mechanisms and identities of the cell types involved have remained unknown, and the validity of the observation has been questioned. Here, we use transplantation of single CD45+ hematopoietic stem cells (HSCs) to demonstrate that the entire circulating myogenic activity in bone marrow is derived from HSCs and their hematopoietic progeny. We also show that ongoing muscle regeneration and inflammatory cell infiltration are required for HSC-derived contribution, which does not occur through a myogenic stem cell intermediate. Using a lineage tracing strategy, we show that myofibers are derived from mature myeloid cells in response to injury. Our results indicate that circulating myeloid cells, in response to inflammatory cues, migrate to regenerating skeletal muscle and stochastically incorporate into mature myofibers.
TL;DR: The hypothesis that stem cells possess a wide-open chromatin structure to maintain their multipotentiality, which is progressively quenched as they go down a particular pathway of differentiation, is supported.
TL;DR: The role of the Bcl-2 protein family and to a lesser extent that of death receptors (members of the tumor necrosis factor receptor family with a death domain) in the control of lymphoid and myeloid cell survival is described.
Abstract: Apoptotic cell death plays a critical role in the development and functioning of the immune system. During differentiation, apoptosis weeds out lymphocytes lacking useful antigen receptors and those expressing dangerous ones. Lymphocyte death is also involved in limiting the magnitude and duration of immune responses to infection. In this review, we describe the role of the Bcl-2 protein family, and to a lesser extent that of death receptors (members of the tumor necrosis factor receptor family with a death domain), in the control of lymphoid and myeloid cell survival. We also consider the pathogenic consequences of failure of apoptosis in the immune system.
TL;DR: The results suggest a model in which STAT3 has critical roles in the development and regulation of innate immunity, and deletion of STAT3 during hematopoiesis results in abnormalities in myeloid cells and causes Crohn's disease-like pathogenesis.
Abstract: Signal transducer and activator of transcription 3 (STAT3) is a key transcriptional mediator for many cytokines and is essential for normal embryonic development. We have generated a unique strain of mice with tissue-specific disruption of STAT3 in bone marrow cells during hematopoiesis. This specific STAT3 deletion causes death of these mice within 4–6 weeks after birth with Crohn's disease-like pathogenesis in both the small and large intestine, including segmental inflammatory cell infiltration, ulceration, bowel wall thickening, and granuloma formation. Deletion of STAT3 causes significantly increased cell autonomous proliferation of cells of the myeloid lineage, both in vivo and in vitro. Most importantly, Stat3 deletion during hematopoiesis causes overly pseudoactivated innate immune responses. Although inflammatory cytokines, including tumor necrosis factor α and IFN-γ, are overly produced in these mice, the NAPDH oxidase activity, which is involved in antimicrobial and innate immune responses, is inhibited. The signaling responses to lipopolysaccharide are changed in the absence of STAT3, leading to enhanced NF-κB activation. Our results suggest a model in which STAT3 has critical roles in the development and regulation of innate immunity, and deletion of STAT3 during hematopoiesis results in abnormalities in myeloid cells and causes Crohn's disease-like pathogenesis.
TL;DR: Gfi-1 not only promotes differentiation of neutrophils but also antagonizes traits of the alternate monocyte/macrophage program.
TL;DR: It is shown by chromatin immunoprecipitation, gel shift, reporter assays and elevated expression of ELA2 in vivo in neutropenic individuals that GFI1 represses ELA1, linking these two genes in a common pathway involved in myeloid differentiation.
Abstract: Mice lacking the transcriptional repressor oncoprotein Gfi1 are unexpectedly neutropenic1,2. We therefore screened GFI1 as a candidate for association with neutropenia in affected individuals without mutations in ELA2 (encoding neutrophil elastase), the most common cause of severe congenital neutropenia (SCN; ref. 3). We found dominant negative zinc finger mutations that disable transcriptional repressor activity. The phenotype also includes immunodeficient lymphocytes and production of a circulating population of myeloid cells that appear immature. We show by chromatin immunoprecipitation, gel shift, reporter assays and elevated expression of ELA2 in vivo in neutropenic individuals that GFI1 represses ELA2, linking these two genes in a common pathway involved in myeloid differentiation.
TL;DR: It is shown that MLL fusions also generate a distinct genetic subtype of T-lineage ALL (MLL T-ALL), in which leukemic cells are characterized by an early arrest in thymocyte differentiation, with suggestive evidence of commitment to the gammadelta lineage.
TL;DR: The category AML with 11q23/MLL abnormalities accounts for 2.8% of unselected AML, is closely associated with monocytic differentiation, and has a dismal prognosis.
TL;DR: Interestingly, other parts of the transcriptional program involve novel, IL-3-independent pathways that antagonize differentiation-inducing effects of wild-type Flt3, which should ease the development of specific therapies.
TL;DR: It is shown that Bcl11a is essential for postnatal development and normal lymphopoiesis and may also function as a non-autonomous T cell tumor suppressor gene.
Abstract: Bcl11a (also called Evi9) functions as a myeloid or B cell proto-oncogene in mice and humans, respectively. Here we show that Bcl11a is essential for postnatal development and normal lymphopoiesis. Bcl11a mutant embryos lack B cells and have alterations in several types of T cells. Phenotypic and expression studies show that Bcl11a functions upstream of the transcription factors Ebf1 and Pax5 in the B cell pathway. Transplantation studies show that these defects in Bcl11a mutant mice are intrinsic to fetal liver precursor cells. Mice transplanted with Bcl11a-deficient cells died from T cell leukemia derived from the host. Thus, Bcl11a may also function as a non-autonomous T cell tumor suppressor gene.
TL;DR: The data obtained in the BALB-neuT model of naturally occurring carcinogenesis show that tumor-associated immune suppression is secondary to a more general alteration of host hematopoiesis, conditioned by tumor-secreted soluble factors.
TL;DR: Clinical-scale ex vivo expansion of UCB is feasible, and the administration of ex vivo-expanded cells is well tolerated, and a randomized phase 2 study will determine whether augmenting conventional UCB transplants with ex vivo -expanded UCB cells is beneficial.
TL;DR: Quiescent leukemic cells, including NOD/SL-ICs, are present in most AML patients, and their spontaneous entry into active cell cycle in short-term culture might be explained by the deregulated GF signaling present in many AMLs.
TL;DR: The ability of both myDCs and pcDCs from HIV-1-infected patients to stimulate allogeneic T-lymphocyte proliferation in a 6-day mixed leukocyte reaction was severely impaired, but was not mediated by secondary infection of T lymphocytes.
TL;DR: Patients with AML blasts expressing high levels of VEGF mRNA by quantitative polymerase chain reaction (PCR) had a significantly higher response rate and reduction of bone marrow microvessel density than patients with low V EGF expression consistent with the antiangiogenic effects of SU5416.
TL;DR: Results support a role for combinatorial effects by Notch and cytokine-induced signaling pathways in regulating hematopoietic cell fate and suggest the usefulness of Notch ligand in increasing hematopolietic precursor numbers for clinical stem-cell transplantation.
TL;DR: It is indicated that overproduction of IL-12p40, which induces potent Th1 responses, is essential for the development of chronic enterocolitis in Stat3 mutant mice.
Abstract: Stat3 plays an essential role in IL-10 signaling pathways. A myeloid cell-specific deletion of Stat3 resulted in inflammatory cytokine production and development of chronic enterocolitis with enhanced Th1 responses in mice. In this study, we analyzed the mechanism by which a Stat3 deficiency in myeloid cells led to the induction of chronic enterocolitis in vivo. Even in the absence of Stat1, which is essential for IFN-γ signaling pathways, Stat3 mutant mice developed chronic enterocolitis. TNF-α/Stat3 double-mutant mice developed severe chronic enterocolitis with enhanced Th1 cell development. IL-12p40/Stat3 double-mutant mice, however, showed normal Th1 responses and no inflammatory change in the colon. RAG2/Stat3 double-mutant mice did not develop enterocolitis, either. These findings indicate that overproduction of IL-12p40, which induces potent Th1 responses, is essential for the development of chronic enterocolitis in Stat3 mutant mice. Furthermore, enterocolitis was significantly improved and IFN-γ production by T cells was reduced in TLR4/Stat3 double-mutant mice, indicating that TLR4-mediated recognition of microbial components triggers aberrant IL-12p40 production by myeloid cells, leading to the development of enterocolitis. Thus, this study clearly established a sequential innate and acquired immune mechanism for the development of Th1-dependent enterocolitis.
TL;DR: PU.1 is down-regulated by AML1-ETO in t(8;21) myeloid leukemia, whereas overexpression of PU.1 restores normal differentiation.
TL;DR: The findings strongly suggest that the WT1 assay is very useful for the prediction and management of relapse following allogeneic stem cell transplantation regardless of the presence of chimeric gene markers.