86 research outputs found
GRK6 deficiency is associated with enhanced CXCR4-mediated neutrophil chemotaxis in vitro and impaired responsiveness to G-CSF in vivo
An in vitro model for cytogenetic conversion in CML: Interferon-alpha preferentially inhibits the outgrowth of malignant stem cells preserved in long-term culture
An in vitro model for cytogenetic conversion in CML: Interferon-alpha preferentially inhibits the outgrowth of malignant stem cells preserved in long-term culture
GATA-2 Plays Two Functionally Distinct Roles during the Ontogeny of Hematopoietic Stem Cells
GATA-2 is an essential transcription factor in the hematopoietic system that is expressed in hematopoietic stem cells (HSCs) and progenitors. Complete deficiency of GATA-2 in the mouse leads to severe anemia and embryonic lethality. The role of GATA-2 and dosage effects of this transcription factor in HSC development within the embryo and adult are largely unexplored. Here we examined the effects of GATA-2 gene dosage on the generation and expansion of HSCs in several hematopoietic sites throughout mouse development. We show that a haploid dose of GATA-2 severely reduces production and expansion of HSCs specifically in the aorta-gonad-mesonephros region (which autonomously generates the first HSCs), whereas quantitative reduction of HSCs is minimal or unchanged in yolk sac, fetal liver, and adult bone marrow. However, HSCs in all these ontogenically distinct anatomical sites are qualitatively defective in serial or competitive transplantation assays. Also, cytotoxic drug-induced regeneration studies show a clear GATA-2 dose–related proliferation defect in adult bone marrow. Thus, GATA-2 plays at least two functionally distinct roles during ontogeny of HSCs: the production and expansion of HSCs in the aorta-gonad-mesonephros and the proliferation of HSCs in the adult bone marrow
Embryonal sub-region-derived stromal cell from novel temperature-sensitive SV40 T antigen transgenic mice suppport hematopoiesis
Embryonal sub-region-derived stromal cell from novel temperature-sensitive SV40 T antigen transgenic mice suppport hematopoiesis
Comparison of different busulfan analogues for depletion of hematopoietic stem cells and promotion of donor-type chimerism in murine bone marrow transplant recipients
Sustained receptor activation and hyperproliferation in response to granulocyte colony-stimulating factor (G-CSF) in mice with a severe congenital neutropenia/acute myeloid leukemia-derived mutation in the G-CSF receptor gene
In approximately 20% of cases of severe congenital neutropenia (SCN),
mutations are found in the gene encoding the granulocyte
colony-stimulating factor receptor (G-CSF-R). These mutations introduce
premature stop codons, which result in truncation of 82-98 COOH-terminal
amino acids of the receptor. SCN patients who develop secondary
myelodysplastic syndrome and acute myeloid leukemia almost invariably
acquired a GCSFR mutation, suggesting that this genetic alteration
represents a key step in leukemogenesis. Here we show that an equivalent
mutation targeted in mice (gcsfr-Delta715) results in the selective
expansion of the G-CSF- responsive progenitor (G-CFC) compartment in the
bone marrow. In addition, in vivo treatment of gcsfr-Delta715 mice with
G-CSF results in increased production of neutrophils leading to a
sustained neutrophilia. This hyperproliferative response to G-CSF is
accompanied by prolonged activation of signal transducer and activator of
transcription (STAT) complexes and extended cell surface expression of
mutant receptors due to defective internalization. In view of the
continuous G-CSF treatment of SCN patients, these data provide insight
into why progenitor cells expressing truncated receptors clonally expand
in vivo, and why these cells may be targets for additional genetic events
leading to leukemia
Sustained Receptor Activation and Hyperproliferation in Response to Granulocyte Colony-stimulating Factor (G-CSF) in Mice with a Severe Congenital Neutropenia/Acute Myeloid Leukemia–derived Mutation in the G-CSF Receptor Gene
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