Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Lineage”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 667 records · Page 37Linked to original sources
PubMed2003

CALM-AF10 is a common fusion transcript in T-ALL and is specific to the TCRgammadelta lineage.

The t(10;11)(p13-14;q14-21) associated with CALM-AF10 is considered to be rare and associated with a variety of acute lymphoid and myeloid leukemias. Twelve (9%) of 131 unselected T-cell acute lymphoid leukemias (T-ALLs) expressed CALM-AF10 by reverse transcription-polymerase chain reaction or fluorescence in situ hybridization (or both), including 8% of children and 10% of adults, of whom only half demonstrated a t(10;11) by classical cytogenetics. CALM-AF10 was not found in T-cell-receptor alphabeta (TCRalphabeta) lineage T-ALLs, as defined by expression of TCRalphabeta, cytoplasmic TCRbeta, or TCRbetaVDJ rearrangement in immature cytoplasmic TCRbeta- cases, compared with 19% of TCRgammadelta T-ALLs and 33% of immature delta/gamma T-ALLs. The latter differed from their CALM-AF10- immature counterparts by a CD5+/CD2-phenotype, as found in TCRgammadelta but not TCRalphabeta T-ALLs and in their TCRgamma and TCRdelta configurations, altogether suggesting that CALM-AF10+ immature delta/gammaT-ALLs are TCRgammadelta precursors and that, within T-ALL, CALM-AF10 is specific for this lineage. Nine of 12 immature CALM-AF10 T-ALLs demonstrated 3' fusion transcripts, whereas 6 of 7 TCRgammadelta T-ALLs demonstrated 5' fusion transcripts. The latter retain the AF10 extended LAP/PHD domain necessary for homo-oligomerization. All 8 patients with CALM-AF10+TCRgammadelta T-ALLs are alive, compared with only 3 of 12 with immature CALM-AF10+ T-ALLs. Six CALM-AF10+ non-T acute leukemias all expressed CD7 and demonstrated T-restricted TCRdelta rearrangements, suggesting that they may also be related to the TCRgammadelta lineage. CALM-AF10 is therefore the most common fusion protein in T-ALL. It requires molecular and immunophenotypic characterization for appropriate prognostic evaluation and should be included in diagnostic screening panels of T-ALL and immature acute leukemias. Analysis of immature CALM-AF10+ leukemias will also facilitate analysis of the early stages of development of the TCRgammadelta lineage.

3' Untranslated Regions↗
PubMed2003

Pax5 determines B- versus T-cell fate and does not block early myeloid-lineage development.

Progenitor B cells deficient in Pax5 are developmentally multipotent, suggesting that Pax5 is necessary to maintain commitment to the B-cell lineage. Commitment may be mediated, in part, by Pax5 repression of myeloid-specific genes. To determine whether Pax5 expression in multipotential cells is sufficient to restrict development to the B-cell lineage in vivo, we enforced expression of Pax5 in hematopoietic stem cells using a retroviral vector. Peripheral blood analysis of all animals reconstituted with Pax5-expressing cells indicated that more than 90% of Pax5-expressing cells were B220+ mature B cells that were not malignant. Further analysis showed that Pax5 completely blocked T-lineage development in the thymus but did not inhibit myelopoiesis or natural killer (NK) cell development in bone marrow. These results implicate Pax5 as a critical regulator of B- versus T-cell developmental fate and suggest that Pax5 may promote commitment to the B-cell lineage by mechanisms that are independent of myeloid gene repression.

Animals↗
PubMed2005

Delta-like1-induced Notch1 signaling regulates the human plasmacytoid dendritic cell versus T-cell lineage decision through control of GATA-3 and Spi-B.

Human early thymic precursors have the potential to differentiate into multiple cell lineages, including T cells and plasmacytoid dendritic cells (pDCs). This decision is guided by the induction or silencing of lineage-specific transcription factors. The ETS family member Spi-B is a key regulator of pDC development, whereas T-cell development is critically dependent on GATA-3. Here we show that triggering of the Notch1 signaling pathway by Delta-like1 controls the T/pDC lineage decision by regulating the balance between these factors. CD34+ CD1a- thymic progenitor cells express Notch1, but down-regulate this receptor when differentiating into pDCs. On coculture with stromal cell lines expressing either human Delta-like1 (DL1) or Jagged1 (Jag1) Notch ligands, thymic precursors express GATA-3 and develop into CD4+ CD8+ TCRalphabeta+ T cells. On the other hand, DL1, but not Jag1, down-regulates Spi-B expression, resulting in impaired development of pDCs. The Notch1-induced block in pDC development can be relieved through the ectopic expression of Spi-B. These data indicate that DL1-induced activation of the Notch1 pathway controls the lineage commitment of early thymic precursors by altering the levels between Spi-B and GATA-3.

Antigens, CD34↗
PubMed2005

The expression of 70 apoptosis genes in relation to lineage, genetic subtype, cellular drug resistance, and outcome in childhood acute lymphoblastic leukemia.

Childhood acute lymphoblastic leukemia (ALL) consists of various subtypes that respond differently to cytotoxic drugs and therefore have a markedly different clinical outcome. We used microarrays to investigate, in 190 children with ALL at initial diagnosis, whether 70 key apoptosis genes were differentially expressed between leukemic subgroups defined by lineage, genetic subtype, in vitro drug resistance, and clinical outcome. The expression of 44 of 70 genes was significantly different in T-versus B-lineage ALL, 22 genes differed in hyperdiploid versus nonhyperdiploid, 16 in TEL-AML1-positive versus-negative, and 13 in E2A-rearranged versus germ-line B-lineage ALL. Expression of MCL1 and DAPK1 was significantly associated with prednisolone sensitivity, whereas BCL2L13, HRK, and TNF were related to L-asparaginase resistance. BCL2L13 overexpression was also associated with unfavorable clinical outcome (P < .001). Multivariate analysis including known risk factors revealed that BCL2L13 expression was an independent prognostic factor (P = .011). The same trend was observed in a validation group of 92 children with ALL treated on a different protocol at St Jude (P = .051). In conclusion, ALL subtypes have a unique expression pattern of apoptosis genes and our data suggest that selective genes are linked to cellular drug resistance and prognosis in childhood B-lineage ALL.

Apoptosis↗
PubMed2006

The megakaryocyte lineage originates from hemangioblast precursors and is an integral component both of primitive and of definitive hematopoiesis.

In the adult, platelets are derived from unipotential megakaryocyte colony-forming cells (Meg-CFCs) that arise from bipotential megakaryocyte/erythroid progenitors (MEPs). To better define the developmental origin of the megakaryocyte lineage, several aspects of megakaryopoiesis, including progenitors, maturing megakaryocytes, and circulating platelets, were examined in the murine embryo. We found that a majority of hemangioblast precursors during early gastrulation contains megakaryocyte potential. Combining progenitor assays with immunohistochemical analysis, we identified 2 waves of MEPs in the yolk sac associated with the primitive and definitive erythroid lineages. Primitive MEPs emerge at E7.25 along with megakaryocyte and primitive erythroid progenitors, indicating that primitive hematopoiesis is bilineage in nature. Subsequently, definitive MEPs expand in the yolk sac with Meg-CFCs and definitive erythroid progenitors. The first GP1bbeta-positive cells in the conceptus were identified in the yolk sac at E9.5, while large, highly reticulated platelets were detected in the embryonic bloodstream beginning at E10.5. At this time, the number of megakaryocyte progenitors begins to decline in the yolk sac and expand in the fetal liver. We conclude that the megakaryocyte lineage initially originates from hemangioblast precursors during early gastrulation and is closely associated both with primitive and with definitive erythroid lineages in the yolk sac prior to the transition of hematopoiesis to intraembryonic sites.

Animals↗
PubMed2005

Lineage promiscuity and plasticity in hematopoietic development.

Hematopoiesis has provided a valuable model for understanding how genetic programs are established to decide cell fates in multipotent stem or progenitor cells. The identification of common myeloid and lymphoid progenitors has allowed us to directly assess the regulatory mechanisms of lineage commitment. Multiple genes of hematopoietic lineages, including transcription factors, are coexpressed in hematopoietic stem cells and progenitors, a phenomenon referred to as "lineage priming." The accessibility for multiple transcription factors promiscuously allows flexibility in cell fate commitments at the multipotent stages. The changes in the expression levels and timing of transcription factors can induce lineage conversion of committed cells, indicating that the regulation of transcription factors might be primarily critical for maintaining hierarchical hematopoietic development.

Animals↗
PubMed2005

Genetic analysis of interactions between the somitic muscle, cartilage and tendon cell lineages during mouse development.

Proper formation of the musculoskeletal system requires the coordinated development of the muscle, cartilage and tendon lineages arising from the somitic mesoderm. During early somite development, muscle and cartilage emerge from two distinct compartments, the myotome and sclerotome, in response to signals secreted from surrounding tissues. As the somite matures, the tendon lineage is established within the dorsolateral sclerotome, adjacent to and beneath the myotome. We examine interactions between the three lineages by observing tendon development in mouse mutants with genetically disrupted muscle or cartilage development. Through analysis of embryos carrying null mutations in Myf5 and Myod1, hence lacking both muscle progenitors and differentiated muscle, we identify an essential role for the specified myotome in axial tendon development, and suggest that absence of tendon formation in Myf5/Myod1 mutants results from loss of the myotomal FGF proteins, which depend upon Myf5 and Myod1 for their expression, and are required, in turn, for induction of the tendon progenitor markers. Our analysis of Sox5/Sox6 double mutants, in which the chondroprogenitors are unable to differentiate into cartilage, reveals that the two cell fates arising from the sclerotome, axial tendon and cartilage are alternative lineages, and that cartilage differentiation is required to actively repress tendon development in the dorsolateral sclerotome.

Animals↗
PubMed1997

Mutations in lottchen cause cell fate transformations in both neuroblast and glioblast lineages in the Drosophila embryonic central nervous system.

The Drosophila embryonic central nervous system (CNS) develops from a stereotyped pattern of neuronal progenitor cells called neuroblasts (NB). Each NB has a unique identity that is defined by the time and position of its formation and a characteristic combination of genes it expresses. Each NB generates a specific lineage of neurons and/or glia. Here we describe the genetic and phenotypic analysis of lottchen (ltt), a novel gene whose loss of function causes a change in the identity of at least one NB as well as cell fate transformations within the lateral glioblast lineage. In wildtype embryos the parental NB of the motoneuron RP2 is NB4-2. ltt embryos are distinguished by an additional RP2-like neuron which appears later in development. We show that the two RP2 neurons are derived from two distinct GMC4-2a-like cells that do not share the same parental NB, indicating that a second NB has acquired the potential to produce a GMC and a neuron which is normally restricted to the NB4-2 lineage. Moreover, the ltt mutations lead to a loss of correctly specified longitudinal glia; this coincides with severely defective longitudinal connectives. Therefore, lottchen plays a role in specifying the identity of both neuroblast and glioblast lineages in the Drosophila embryonic CNS. We discuss the possibility that ltt may act to differentiate NB identity along the medial lateral axis.

Alleles↗
PubMed2001

Cell lineage determination in the mouse.

During the peri-implantation development of the mouse embryo from the blastocyst through gastrulation, Pou5f1 (OCT-4) down-regulation is closely linked to the initial step of lineage allocation to extraembryonic and embryonic somatic tissues. Subsequently, differentiation of the lineage precursors is subject to inductive tissue interactions and intercellular signalling that regulate cell proliferation and the acquisition of lineage-specific morphological and molecular characteristics. A notable variation of this process of lineage specification is the persistence of Pou5f1 activity throughout the differentiation of the primordial germ cells, which may underpin their ability to produce pluripotent progeny either as stem cells (embryonic germ cells) in vitro or as gametes in vivo. Nevertheless, intercellular signalling still plays a critical role in the specification of the primordial germ cells. The findings that primordial germ cells can be induced from any epiblast cells and that they share common progenitors with other somatic cells provide compelling evidence for the absence of a pre-determined germ line in the mouse embryo.

Animals↗
PubMed2006

Notch promotes neural lineage entry by pluripotent embryonic stem cells.

A central challenge in embryonic stem (ES) cell biology is to understand how to impose direction on primary lineage commitment. In basal culture conditions, the majority of ES cells convert asynchronously into neural cells. However, many cells resist differentiation and others adopt nonneural fates. Mosaic activation of the neural reporter Sox-green fluorescent protein suggests regulation by cell-cell interactions. We detected expression of Notch receptors and ligands in mouse ES cells and investigated the role of this pathway. Genetic manipulation to activate Notch constitutively does not alter the stem cell phenotype. However, upon withdrawal of self-renewal stimuli, differentiation is directed rapidly and exclusively into the neural lineage. Conversely, pharmacological or genetic interference with Notch signalling suppresses the neural fate choice. Notch promotion of neural commitment requires parallel signalling through the fibroblast growth factor receptor. Stromal cells expressing Notch ligand stimulate neural specification of human ES cells, indicating that this is a conserved pathway in pluripotent stem cells. These findings define an unexpected and decisive role for Notch in ES cell fate determination. Limiting activation of endogenous Notch results in heterogeneous lineage commitment. Manipulation of Notch signalling is therefore likely to be a key factor in taking command of ES cell lineage choice.

Animals↗
PubMed2025

MitoTracer facilitates the identification of informative mitochondrial mutations for precise lineage reconstruction.

Mitochondrial (MT) mutations serve as natural genetic markers for inferring clonal relationships using single cell sequencing data. However, the fundamental challenge of MT mutation-based lineage tracing is automated identification of informative MT mutations. Here, we introduced an open-source computational algorithm called "MitoTracer", which accurately identified clonally informative MT mutations and inferred evolutionary lineage from scRNA-seq or scATAC-seq samples. We benchmarked MitoTracer using the ground-truth experimental lineage sequencing data and demonstrated its superior performance over the existing methods measured by high sensitivity and specificity. MitoTracer is compatible with multiple single cell sequencing platforms. Its application to a cancer evolution dataset revealed the genes related to primary BRAF-inhibitor resistance from scRNA-seq data of BRAF-mutated cancer cells. Overall, our work provided a valuable tool for capturing real informative MT mutations and tracing the lineages among cells.

Humans↗
PubMed2002

Pancreatic cell lineage analyses in mice.

Considerable knowledge of the ontogeny of the endocrine pancreas has been gained in recent years, mainly through the use of two complementary genetic approaches in transgenic mice: gene inactivation or overexpression (to assess gene function) and genetic labeling of precursor cells (to determine cell lineages). In recent years, in vivo Cre/loxP-based direct cell tracing experiments show that (i) all pancreatic cells differentiate from pdx1-expressing precursors, (ii) p48 is involved in the exocrine and endocrine pancreatic lineages, (iii) islet endocrine cells derive from ngn3-expressing progenitor cells, and (iv) insulin cells do not derive from glucagon- expressing progenitors. Lineage analyses allow the identification of progenitor cells from which mature cell types differentiate. Once identified, such progenitors can be labeled and isolated, and their differentiation and gene expression profiles studied in vitro. Understanding pancreatic cell lineages is highly relevant for future cell replacement therapies in diabetic patients, helping to define the identity of putative (endodermal) pancreatic stem cells.

Animals↗
PubMed2002

Somatic epidermal stem cells can produce multiple cell lineages during development.

It has been demonstrated that several types of somatic stem cells have the remarkable capacity to differentiate into other types of tissues. We demonstrate here that stem cells from the skin, the largest organ of the body, have the capacity to form multiple cell lineages during development. Using our recently developed sorting technique, we isolated viable homogeneous populations of somatic epidermal stem and transient amplifying cells from the skin of 3-day old transgenic mice, who carried the enhanced green fluorescent protein transgene, and injected stem, TA, or unsorted basal epidermal cells into 3.5-day C57BL/6 blastocysts. Only the stem-injected blastocysts produced mice with GFP(+) cells in their tissues. We found GFP(+) cells in ectodermal, mesenchymal, and neural-crest-derived tissues in E13.5 embryos, 13-day-old neonates, and 60-day-old adult mice, proving that epidermal stem cells survived the blastocyst injection and multiplied during development. Furthermore, the injected stem cells altered their epidermal phenotype and expressed the appropriate proteins for the tissues into which they developed, demonstrating that somatic epidermal stem cells have the ability to produce cells of different lineages during development. These data suggest that somatic epidermal stem cells may show a generalized plasticity expected only of embryonic stem cells and that environmental (extrinsic) factors may influence the lineage pathway for somatic stem cells. Thus, the skin could be a source of easily accessible stem cells that are able to be reprogrammed to form multiple cell lineages.

Animals↗
PubMedDate not supplied

SCL expression at critical points in human hematopoietic lineage commitment.

The stem cell leukemia (SCL or tal-1) gene was initially identified as a translocation partner in a leukemia that possessed both lymphoid and myeloid differentiation potential. Mice that lacked SCL expression showed a complete block in hematopoiesis; thus, SCL was associated with hematopoietic stem cell (HSC) function. More recent studies show a role for SCL in murine erythroid differentiation. However, the expression pattern and the role of SCL during early stages of human hematopoietic differentiation are less clear. In this study we chart the pattern of human SCL expression from HSCs, through developmentally sequential populations of lymphoid and myeloid progenitors to mature cells of the hematopoietic lineages. Using recently defined surface immunophenotypes, we fluorescence-activated cell-sorted (FACS) highly purified populations of primary human hematopoietic progenitors for reverse transcription-polymerase chain reaction (RT-PCR) analysis of SCL expression. Our data show that SCL mRNA is easily detectable in all hematopoietic populations with erythroid potential, including HSCs, multipotential progenitors, common myeloid progenitors, megakaryocyte/erythrocyte progenitors, and nucleated erythroid lineage cells. SCL mRNA expression was present but rapidly downregulated in the common lymphoid progenitor and granulocyte/monocyte progenitor populations that lack erythroid potential. SCL expression was undetectable in immature cells of nonerythroid lineages, including pro-B cells, early thymic progenitors, and myeloid precursors expressing the M-CSF receptor. SCL expression was also absent from all mature cells of the nonerythroid lineages. Although low levels of SCL were detected in lymphoid- and myeloid-restricted progenitors, our studies show that abundant SCL expression is normally tightly linked with erythroid differentiation potential.

Animals↗
PubMed2001

What can we learn from leukemia as for the process of lineage commitment in hematopoiesis?

Most contemporary models of hematopoiesis assume lineage fidelity of early progenitor cells. Along with this concept normal hematopoietic cells and the majority of leukemias express exclusively myeloid or lymphoid specific antigens. On the other hand, growing evidence exists challenging the lineage fidelity model. Chronic myeloid leukemia (CML) in the blast crisis may switch to acute lymphoblastic leukemia (ALL) and as a result of the chemotherapy ALL may converse to acute myeloid leukemia (AML). Furthermore, a substantial portion of leukemia cases, named acute mixed-lineage leukemia (AMLL), show simultaneous expression of both myeloid and lymphoid antigens. Immunoglobulin (Ig) and T-cell receptor (TCR) gene rearrangements, correlating with myeloid-lymphoid immunophenotype in AMLL, support the hypothesis of lineage infidelity of early progenitor cells, rather than the aberrant antigen expression. Based on a detailed characterization of AMLL we present a modified model of a "common myeloid/lymphoid progenitor cell". This hypothetical very early hematopoietic progenitor cell shows a transient expression of myeloid and B- or T-lymphoid antigen and may also have rearranged its Ig and/or TCR genes. Subsequently, myeloid or lymphoid markers are downregulated and the hematopoietic cell enters either myeloid, T-lymphoid or B-lymphoid differentiation pathway.

Animals↗
PubMed2000

Peroxisome proliferator activator receptor-gamma agonists and 15-deoxy-Delta(12,14)(12,14)-PGJ(2) induce apoptosis in normal and malignant B-lineage cells.

The research described herein evaluates the expression and functional significance of peroxisome proliferator activator receptor-gamma (PPAR-gamma) on B-lineage cells. Normal mouse B cells and a variety of B lymphoma cells reflective of stages of B cell differentiation (e.g., 70Z/3, CH31, WEHI-231, CH12, and J558) express PPAR-gamma mRNA and, by Western blot analysis, the 67-kDa PPAR-gamma protein. 15-Deoxy-Delta(12,14)-PGJ(2) (15d-PGJ(2)), a PPAR-gamma agonist, has a dose-dependent antiproliferative and cytotoxic effect on normal and malignant B cells as shown by [(3)H]thymidine and 3-[4,5-dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide assays. Only PPAR-gamma agonists (thiazolidinediones), and not PPAR-alpha agonists, mimicked the effect of 15d-PGJ(2) on B-lineage cells, indicating that the mechanism by which 15d-PGJ(2) negatively affects B-lineage cells involves in part PPAR-gamma. The mechanism by which PPAR-gamma agonists induce cytotoxicity is via apoptosis, as shown by annexin V staining and as confirmed by DNA fragmentation detected using the TUNEL assay. Interestingly, addition of PGF(2alpha), which was not known to affect lymphocytes, dramatically attenuated the deleterious effects of PPAR-gamma agonists on B lymphomas. Surprisingly, 15d-PGJ(2) induced a massive increase in nuclear mitogen-activated protein kinase activation, and pretreatment with PGF(2alpha) blunted the mitogen-activated protein kinase activation. This is the first study evaluating PPAR-gamma expression and its significance on B lymphocytes. PPAR-gamma agonists may serve as a counterbalance to the stimulating effects of other PGs, namely PGE(2), which promotes B cell differentiation. Finally, the use of PGs, such as 15d-PGJ(2), and synthetic PPAR-gamma agonists to induce apoptosis in B-lineage cells may lead to the development of novel therapies for fatal B lymphomas.

Animals↗
PubMed2004

Allelic exclusion at the TCR delta locus and commitment to gamma delta lineage: different modalities apply to distinct human gamma delta subsets.

Expression of a beta-chain, as a pre-TCR, in T cell precursors prevents further rearrangements on the alternate beta allele through a strict allelic exclusion process and enables precursors to undergo differentiation. However, whether allelic exclusion applies to the TCR delta locus is unknown and the role of the gamma delta TCR in gamma delta lineage commitment is still unclear. Through the analysis of the rearrangement status of the TCR gamma, delta, and beta loci in human gamma delta T cell clones, expressing either the TCR V delta 1 or V delta 2 variable regions, we show that the rate of partial rearrangements at the delta locus is consistent with an allelic exclusion process. The overrepresentation of clones with two functional TCR gamma chains indicates that a gamma delta TCR selection process is required for the commitment of T cell precursors to the gamma delta lineage. Finally, while complete TCR beta rearrangements were observed in several V delta 2 T cell clones, these were seldom found in V delta 1 cells. This suggests a competitive alpha beta/gamma delta lineage commitment in the former subset and a precommitment to the gamma delta lineage in the latter. We propose that these distinct behaviors are related to the developmental stage at which rearrangements occur, as suggested by the patterns of accessibility to recombination sites that characterize the V delta 1 and V delta 2 subsets.

Adult↗
PubMed2004

Ikaros null mice display defects in T cell selection and CD4 versus CD8 lineage decisions.

Previous evidence suggested that the hemopoietic-specific nuclear factor Ikaros regulates TCR signaling thresholds in mature T cells. In this study, we test the hypothesis that Ikaros also sets TCR signaling thresholds to regulate selection events and CD4 vs CD8 lineage determination in developing thymocytes. Ikaros null mice were crossed to three lines of TCR-transgenic mice, and positive selection, negative selection, and CD4 vs CD8 lineage decisions were analyzed. Mice expressing a polyclonal repertoire or a MHC class II-restricted TCR transgene exhibited enhanced positive selection toward the CD4 lineage. Moreover, in the absence of Ikaros, CD4 development can occur with decreased thresholds of TCR signaling. In addition, CD4 single-positive thymocytes were detected in MHC class I-restricted TCR-transgenic Ikaros null mice. To assess the role of Ikaros in negative selection, we analyzed deletion of T cells induced by conventional Ag or by endogenous superantigen. Surprisingly, negative selection was impaired in Ikaros null thymocytes despite evidence of high levels of TCR signal and no intrinsic defect in apoptosis ex vivo. To our knowledge, these data identify Ikaros as the first nuclear factor that plays a critical role in regulating negative selection as well as CD4 vs CD8 lineage decisions during positive selection.

Animals↗