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At least 19 recordsLinked to original sources
PubMed2026

AML1-ETO hijacks a distal enhancer of NAT10 to reprogram glutathione metabolism and sustain leukemia stem cell stemness.

Chromosomal translocations produce oncogenic fusion proteins such as AML1-ETO, which predominantly occupy gene promoters to induce transcriptional reprogramming in leukemia stem cells (LSCs), consequently driving the pathogenesis of t(8;21) acute myeloid leukemia (AML). However, whether AML1-ETO is recruited to additional regulatory DNA elements to orchestrate oncogenic gene expression programs has not been fully addressed. Here, we define AML1-ETO and H3K27ac CUT&Tag landscapes in primary t(8;21) AML CD34+ cells and t(8;21) AML cell lines, revealing AML1-ETO binding at a distal enhancer of the RNA N4-acetylcytidine (ac4C) writer N-acetyltransferase 10 (NAT10), thereby driving its transcriptional activation. Genetic ablation or pharmacological inhibition of NAT10 restricted the survival and self-renewal of LSCs in primary t(8;21) AML CD34+ cells, as well as in a retroviral AML1-ETO9a-driven t(8;21) AML mouse model, establishing NAT10 as a potential therapeutic vulnerability. Mechanistically, NAT10 is recruited to glutathione S-transferase omega 2 (GSTO2) mRNA to catalyze ac4C modification, thereby enhancing transcript stability and reprogramming glutathione metabolism, as demonstrated by ac4C profiling, RNA immunoprecipitation (RIP), and dCas13b-NAT10-based analyses. Silencing of GSTO2 in primary t(8;21) AML CD34+ cells decreased intracellular reduced glutathione (GSH) levels and compromised LSC survival and self-renewal, whereas GSTO2 overexpression or GSH supplementation largely rescued LSC maintenance following NAT10 loss. Collectively, these findings enrich and extend the understanding of AML1-ETO regulatory programs by linking distal enhancer activity to a NAT10-GSTO2 ac4C-GSH axis that integrates epigenomic, posttranscriptional, and metabolic reprogramming to sustain LSC stemness, highlighting this circuit as a potential therapeutic vulnerability in t(8;21) AML.

Humans↗
PubMed1992

Mobilization of circulating haemopoietic cells (blood stem cells) by GM-CSF in patients with malignancies.

Autologous reinfusion of circulating haemopoietic progenitor and stem cells (blood stem cell transplantation) has emerged as an alternative to autologous bone marrow transplantation in a variety of malignant diseases. Major obstacles associated with harvest of blood stem cells by leukapheresis are: 1. relatively high costs, and 2. discomfort caused to the patient, as generally five to ten settings of leukapheresis are necessary to harvest a number of blood stem cells sufficient for haemopoietic restitution following myeloablative therapy. GM-CSF recently has been shown to effectively increase circulating haemopoietic cells, when given subsequent to even highly-toxic therapy. This report summarizes our data on mobilization of blood stem cells by GM-CSF cells in multiple myeloma patients.

Combined Modality Therapy↗
PubMed2024

The L27 domain of MPP7 enhances TAZ-YY1 cooperation to renew muscle stem cells.

Stem cells regenerate differentiated cells to maintain and repair tissues and organs. They also replenish themselves, i.e. self-renew, to support a lifetime of regenerative capacity. Here we study the renewal of skeletal muscle stem cell (MuSC) during regeneration. The transcriptional co-factors TAZ/YAP (via the TEAD transcription factors) regulate cell cycle and growth while the transcription factor YY1 regulates metabolic programs for MuSC activation. We show that MPP7 and AMOT join TAZ and YY1 to regulate a selected number of common genes that harbor TEAD and YY1 binding sites. Among these common genes, Carm1 can direct MuSC renewal. We demonstrate that the L27 domain of MPP7 enhances the interaction as well as the transcriptional activity of TAZ and YY1, while AMOT acts as an intermediate to bridge them together. Furthermore, MPP7, TAZ and YY1 co-occupy the promoters of Carm1 and other common downstream genes. Our results define a renewal program comprised of two progenitor transcriptional programs, in which selected key genes are regulated by protein-protein interactions, dependent on promoter context.

YY1 Transcription Factor↗
PubMed1992

Stem cell factor has histamine releasing activity in rat connective tissue-type mast cells.

Stem cell factor (SCF) was documented to be involved in the growth of mast cells controlled by fibroblasts. We tested the effect of recombinant rat SCF on degranulation from rat peritoneal mast cells (connective tissue-type mast cells: CTMC). SCF induced histamine release (approximately 20% of total histamine content) in a dose-dependent fashion. The release response was relatively rapid and reached a maximum within 5 min. The release showed total dependence on the presence of extracellular phosphatidylserine (PTS). These results reveal that SCF has histamine releasing activity in CTMC.

Animals↗
PubMed1992

Purification and characterization of soluble forms of human and rat stem cell factor recombinantly expressed by Escherichia coli and by Chinese hamster ovary cells.

Stem cell factor (SCF) is a novel, early-acting hematopoietic factor. It was isolated from the medium of a rat cell line in a soluble, processed form (Zsebo et al., 1990, Cell 63, 195). The cloned human and rat genes encode the soluble form plus additional C-terminal amino acids including a hydrophobic transmembrane domain (Martin et al., 1990, Cell 63, 203). We have recombinantly expressed forms of human and rat SCF corresponding to the soluble, processed form in Escherichia coli and in Chinese hamster ovary (CHO) cells. After expression in E. coli, folding and oxidation of the SCF polypeptides are required. The SCFs expressed in CHO cells are secreted into the medium in active state and, like the natural SCF, are glycosylated. Purification of the recombinant SCFs is described. Biological and biochemical characterization includes activity toward responsive human and mouse cell lines, N-terminal amino acid sequences, disulfide bond linkages, and sites of glycosylation.

Amino Acid Sequence↗
PubMed2026

Effect of adding umbilical cord blood derived stem cells to haploidentical stem cell transplant (haplo-cord) on post-transplant survival and graft-versus-host disease in patients with hematological malignancies: A systematic review and meta-analysis.

BACKGROUND AND OBJECTIVES: Haploidentical stem cell transplantation (haplo-SCT) carries a substantial risk of graft-versus-host disease (GvHD), whereas umbilical cord blood (UCB) transplantation offers lower GvHD risk but slower engraftment. The haplo-cord approach combines both graft sources, aiming to mitigate GvHD while ensuring timely engraftment. This meta-analysis compares haplo-cord transplantation with haplo-SCT alone for the treatment of hematological malignancies. METHODS: Four electronic databases and two clinical trial registries were systematically searched. Effect sizes from eligible studies were pooled using odds ratios (ORs) for dichotomous outcomes and hazard ratios (HRs) for time-to-event outcomes. RESULTS: Twelve studies met the inclusion criteria. Haplo-cord was associated with a statistically significant reduction in chronic GvHD (OR = 0.62, 95%-CI: 0.42-0.93), while no significant difference was observed for grade II-IV acute GvHD (OR = 0.75, 95%-CI: 0.52-1.09). Survival outcomes favored haplo-cord, with lower HRs for overall survival (HR = 0.68, 95%-CI: 0.53-0.86) and event-free survival (HR = 0.61, 95%-CI: 0.52-0.72), while non-relapse mortality was not significant. Relapse at 3 years was significantly lower with haplo-cord (OR = 0.54, 95%-CI: 0.35-0.82). Haplo-cord also demonstrated higher day-30 engraftment, along with lower relapse-related and GvHD-related mortality, while CMV and EBV viremia showed no difference between groups. CD34 selection in the haplo graft significantly influenced effect sizes and heterogeneity in both subgroup analyses and meta-regression for acute GvHD. CONCLUSION: Haplo-cord transplantation improves GvHD outcomes, survival, and relapse risk compared with haplo-SCT alone. However, whether protocol optimization, possibly via CD34 selection, confers additional benefit remains uncertain and requires confirmation in future studies.

Humans↗
PubMed1976

Tumor virus effects on immunocyte precursor cells. Hemopoietic stem cell behavior and leukemogenic susceptibility.

Studies of Rauscher virus-induced erythroleukemia have demonstrated immunodepressive effects in the host and enhanced leukemogenesis with adjuvant administration. These observations led to the study of leukemic development in the NZB strain as a natural model of the experimentally adjuvant-stimulated animal. The results of such investigation would attribute the increased susceptibility of NZB mice to the possession of an enlarged population of pluripotent hemopoietic stem cells in active cell cycle. Studies with radiation chimeras have further shown that elevated endogenous spleen colony formation, the increased potential for autoimmunity, and for susceptibility to Rauscher viral leukemogenesis are all linked through the NZB hemopoietic system. It is concluded that the presence of an enlarged compartment of cyclically active stem cells may be an etiologic factor in the susceptibility to both virus-induced leukemia and the development of autoimmune disease.

Adjuvants, Immunologic↗
PubMed1979

Surface antigens of murine hemopoietic stem cells. I. Cross reactivity of antisera against differentiated hemopoietic cells with bone marrow stem cells.

A model of multiply marked hemopoietic stem cells proposed by Till (1) has been tested with respect to antisera raised against differentiated murine hemopoietic cells. When absorbed with erythrocytes, antisera against CBA mouse lymph node lymphocytes, thymocytes, peritoneal macrophages and platelets cross-reacted strongly with pluripotent stem cells (CFUs) in bone marrow as determined by inhibition of spleen colony formation in lethally irradiated mice. Absorption of ATS, antimacrophage serum and antiplatelet serum with hemopoietic cells other than those used to prepare the antisera (e.g., ATS with neutrophils and platelets, antimacrophage serum with neutrophils, thymocytes and platelets and antiplatelet serum with neutrophils and thymocytes) did not reduce the activity of these antisera for CFUs whereas absorption with the inoculating cell type greatly reduced anti-stem cell activity. Absorption of these antisera with non-hemopoietic tissues such as brain, kidney, liver and testis in general had little effect on antistem cell activity, although a significant loss of activity was observed following absorption of antiplatelet serum with kidney. The antistem cell activity in ATS, antimacrophage serum and antiplatelet serum does not appear to be caused by antibodies against histocompatibility antigens sine bone marrow stem cells from histoincompatible C57BL and Balb/c mice were also sensitive to antisera against CBA mouse hemopoietic cells. In contrast to these findings, antisera against erythrocytes showed little cross-reactivity with CFUs, indicating that few antigens are held in common between erythrocytes and CFUs. We propose that nucleated hemopoietic cells and platelets retain cell line specific antigens in common with pluripotent stem cells from which they were derived, and that the continued expression of these antigens during differentiation may be involved in the differentiation process.

Absorption↗
PubMed1992

Changing antigen receptor gene rearrangements in a case of early pre-B cell leukemia: evidence for a tumor progenitor cell with stem cell features and implications for monitoring residual disease.

A case of acute lymphoblastic leukemia (ALL) was encountered in which the two clonal gamma T-cell receptor gene (TCR gamma) rearrangements found in bone marrow (BM) samples at relapse both differed from the single clonal TCR gamma rearrangement present in BM obtained at diagnosis 5 years previously. In contrast, two clonal Ig heavy chain gene (IgH) rearrangements present at relapse were identical to those present at diagnosis. Comparison of the DNA sequences of the relapse TCR gamma rearrangements with that of the diagnostic TCR gamma rearrangement indicated that they must have been generated de novo from TCR gamma loci in germline configuration. By polymerase chain reaction using clonotypic N-region oligonucleotide primers (N-PCR), cells bearing the diagnosis or relapse TCR gamma rearrangements were undetectable in the sample from the opposite time point. Two BM samples obtained at different times in clinical remission were both devoid of detectable residual tumor when analyzed by N-PCR, indicating a depth of remission of less than 1 tumor cell per 4 x 10(5) BM mononuclear cells. The tumor cells showed a primitive phenotype: T-cell antigen-negative, CALLA/CD10-negative, CD20-negative, CD19-positive, and positive for the myeloid marker My9. This case, which appears to represent a tumor arising from a progenitor cell with both early B-lineage and certain stem cell features, has implications for monitoring residual ALL and possibly also for treatment of the disease.

Adolescent↗
PubMed1992

Searching for hematopoietic stem cells: evidence that Thy-1.1lo Lin- Sca-1+ cells are the only stem cells in C57BL/Ka-Thy-1.1 bone marrow.

Hematopoietic stem cells (HSCs) are defined in mice by three activities: they must rescue lethally irradiated mice (radioprotection), they must self-renew, and they must restore all blood cell lineages permanently. We initially demonstrated that HSCs were contained in a rare (approximately 0.05%) subset of bone marrow cells with the following surface marker profile: Thy-1.1lo Lin- Sca-1+. These cells were capable of long-term, multi-lineage reconstitution and radioprotection of lethally irradiated mice with an enrichment that mirrors their representation in bone marrow, namely, 1,000-2,000-fold. However, the experiments reported did not exclude the possibility that stem cell activity may also reside in populations that are Thy-1.1-, Sca-1-, or Lin+. In this article stem cell activity was determined by measuring: (a) radioprotection provided by sorted cells; (b) long-term, multi-lineage reconstitution of these surviving mice; and (c) long-term, multi-lineage reconstitution by donor cells when radioprotection is provided by coinjection of congenic host bone marrow cells. Here we demonstrate that HSC activity was detected in Thy-1.1+, Sca-1+, and Lin- fractions, but not Thy-1.1-, Sca-1-, or Lin+ bone marrow cells. We conclude that Thy-1.1lo Lin- Sca-1+ cells comprise the only adult C57BL/Ka-Thy-1.1 mouse bone marrow subset that contains pluripotent HSCs.

Animals↗
PubMedDate not supplied

Formation of haematopoietic microenvironment and haematopoietic stem cells from single human bone marrow stem cells.

Haematopoietic stem cells are a population of cells capable both of self renewal and of differentiation into a variety of haematopoietic lineages. Enrichment techniques of human haematopoietic stem cells have used the expression of CD34, present on bone marrow progenitor cells. But most CD34+ bone marrow cells are committed to their lineage, and more recent efforts have focused on the precise characterization of the pluripotent subset of CD34+ cells. Here we report the characterization of two distinct subsets of pluripotent stem cells from human fetal bone marrow, a CD34+, HLA-DR+, CD38- subset that can differentiate into all haematopoietic lineages, and a distinct more primitive subset, that is CD34+, HLA-DR-, CD38-, that can differentiate into haematopoietic precursors and stromal cells capable of supporting the differentiation of these precursors. These data represent, to our knowledge, the first identification of a single cell capable of reconstituting the haematopoietic cells and their associated bone marrow microenvironment.

ADP-ribosyl Cyclase↗
PubMed1979

Antibodies against pluripotent stem cells: their use in studying stem cell function.

The biologic characteristics and specificity of rabbit anti-mouse brain (RAMB) serum for pluripotent hemopoietic stem cells (CFU-s) is reviewed. The application of RAMB serum to the functional analysis of stem cell differentiation and self renewal characteristics is discussed. Preliminary data are presented which suggest the existence of two stem cell subcompartments. The majority of stem cells express membrane determinants that are detected by RAMB serum. A minor (5%-10%) stem cell subpopulation lacks the stem cell antigen and exhibits a greater self-renewal capacity than those cells expressing the antigen.

Animals↗
PubMed1977

Semicontinuous flow centrifugation for the pheresis of immunocompetent cells and stem cells.

Mononuclear cells from human peripheral blood were purified by semicontinuous flow centrifugation (SCFC) using the Haemonetics model 30 blood cell separator; 64% +/- 7% of the mononuclear cells in 600 ml of peripheral blood were collected in a 30-ml volume. Analysis of sequential 5-ml aliquots of the mononuclear cell concentrate revealed that both immunocompetent cells and granulocytic progenitor cells (CFU-C) were proportional to the cell count throughout the buffy coat. In vitro pheresis of large volumes of human bone marrow resulted in recovery of 63% of the cells, 12% of the hemoglobin, and 84% of the CFU-C in 20% of the original volume. Further centrifugation eliminated 80% of the platelets without loss of cells or CFU-C. SCFC of peripheral blood or bone marrow selectively concentrated mononuclear cells and reduced the contamination by granulocytes and erythrocytes. Large numbers of mononuclear cells can thus be collected for studies in vitro or for cryopreservation and the autologous reconstitution of immunosuppressed or myelosuppressed patients undergoing intensive antitumor therapy.

Antibody-Producing Cells↗
PubMed1990

[Cytogenetic examination of bone marrow cells in stem cell diseases of myelodysplastic syndromes].

Cytogenetic examination of bone marrow cells was performed in 43 patients with myelodysplastic syndrome (MDS). MDS was diagnosed from bone marrow biopsies and smears according to the FAB classification. Of all 43 patients 24 (56%) had clonal karyotype changes including frequently monosomies of chromosomes #5 and #7 as well as interstitial deletions of the long arm of #5, 5 q-. Chromosome aberrations were observed in patients belonging to all FAB-subgroups, e.g. 11/15 patients with RA, 6/10 with RAEB, 5/9 with RAEB/T, and 1/9 with CMMoL. Complex chromosome aberrations involving more than 2 chromosomes occurred predominantly in patients with RAEB/T (4/9) but also in patients with RA (2/15) and RAEB (2/10), and correlated significantly (p less than 0.002) with a shorter survival. No correlation was found between chromosome aberrations and the development of ANLL in 9/43 patients (21%).

Aged↗
PubMed1992

The small heat shock protein hsp25 is accumulated in P19 embryonal carcinoma cells and embryonic stem cells of line BLC6 during differentiation.

Murine embryonal carcinoma and embryonic stem cell lines were investigated with regard to the occurrence of the small heat shock protein hsp25 during cell growth and differentiation. In the embryonal carcinoma cell line F9 considerable constitutive levels of hsp25 were observed which could be slightly increased by treatment with retinoic acid. No hsp25 was found, however, in the embryonal carcinoma cell line PCC4. When analyzing the pluripotent embryonal carcinoma cell line P19 and the pluripotent embryonic stem cell line BLC6, both characterized by high differentiation capacity, no hsp25 was observed under cell culture conditions maintaining the undifferentiated state. Induction of differentiation caused by prolonged cell culture, retinoic acid treatment, or embryoid body formation, however, resulted in an increase of the level of hsp25. The finding that hsp25 is accumulated in a differentiation-dependent manner suggests that this protein is associated with processes involved in differentiation. Therefore, hsp25 can be regarded as a marker of differentiation in the investigated embryonal carcinoma cell line P19 and the embryonic stem cell line BLC6.

Animals↗
PubMed1975

The factors controlling stem cell recirculation. i. Migration of hemopoietic stem cells in adrenalectomized mice.

The influence of bilateral adrenalectomy on hemopoietic stem cell (CFU) migration in mice has been studied. Formation of endogenous spleen colonies in lethally irradiated, leg-shielded mice was sharply increased by prior adrenalectomy, and this increase was not dependent on the volume of shielded bone marrow. Adrenalectomy was shown to increase endogenous spleen colony formation in sublethally irradiated mice as well. However, it had no affect on formation of spleen colonies in lethally irradiated mice injected with syngeneic bone marrow. The CFU content of murine bone marrow decreased acutely after removal of the adrenals, and this decrease was accompanied by a concomitant increase in the peripheral blood and splenic CFU. Thus, adrenalectomy appeared to have no affect on the splenic plating efficiency or proliferative rate of hemopoietic stem cells, but it did result in increased migration of stem cells from the bone marrow to the blood, and thence to the spleen. It is concluded that the adrenal steroids may be of physiologic importance in the regulation of ehmopoietic stem cell migration.

Adrenal Glands↗