Expression and role of FLT3 in regulation of the earliest stage of normal granulocyte-monocyte progenitor development

Böiers, Charlotta; Buza‐Vidas, Natalija; Jensen, Christina T.; Pronk, Cornelis Jan; Kharazi, Shabnam; Wittmann, Lilian; Sitnicka, Ewa; Hultquist, Anne; Jacobsen, Sten Eirik W.

doi:10.1182/blood-2009-12-258756

Cited by 39 publications

(38 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…20 When intercrossed, cells expressing Flt3 and all their progeny (irrespectively of Flt3 expression) will express EYFP. As expected, on the basis of the importance of FLT3 in early lymphoid development, 25 virtually all early thymic progenitors and BM B220 ϩ B-cell progenitors were EYFP ϩ (Figure 2A), and as recently shown, 21 also most preGM and GM progenitors ( Figure 2B). Most notably, all stages of Mk and E progenitors also expressed EYFP at high frequencies ( Figure 2B).…”

Section: Percentmentioning

confidence: 59%

“…BM cells and thymocytes were stained with fluorescence-conjugated antibodies as previously described 1,21,22 and analyzed on a FACS LSRII (BD Biosciences) or sorted on a FACSAriaIIu Special Order Research Products (BD Biosciences). For specifics on the antibodies used and further details, see supplemental Methods (available on the Blood Web site; see the Supplemental Materials link at the top of the online article).…”

Section: Fluorescence-activated Cell Staining and Sortingmentioning

confidence: 99%

See 1 more Smart Citation

FLT3 expression initiates in fully multipotent mouse hematopoietic progenitor cells

Buza‐Vidas

Woll

Hultquist

et al. 2011

Blood

Self Cite

View full text Add to dashboard Cite

Section: Percentmentioning

confidence: 59%

Section: Fluorescence-activated Cell Staining and Sortingmentioning

confidence: 99%

FLT3 expression initiates in fully multipotent mouse hematopoietic progenitor cells

Buza‐Vidas

Woll

Hultquist

et al. 2011

Blood

Self Cite

View full text Add to dashboard Cite

“…Previous work demonstrated a distinct role of FLT3 in early myeloid development. 40 At the stage where the myeloid differentiation block occurs in our model, most pGMPs express FLT3 (or FLT3 ITD in this model). Transition from pGMP to GMP is blocked in this model during early stages of leukemogenesis.…”

Section: Discussionmentioning

confidence: 87%

“…These drawbacks are circumvented in our study that characterizes, for the first time to our knowledge, a mouse model for AML where class I and class II mutations are both Cooperation of Flt3 ITD/ þ and Cebpa K/L in early leukemogenesis During the preleukemic phase (Figure 6), Cebpa K/L mutations promote a modest expansion of HSCs and a much more substantial expansion of MPPs (middle panel, Figure 6). FLT3 ITD (and FLT3), which is expressed in MPPs and pGMPs, 40,41 amplified this effect and caused further expansion of MPPs (right panel, Figure 6). Cebpa K/L mutant HSCs can upregulate erythroid-associated genes while granulocyte/ macrophage-associated genes are downregulated, resulting in a block at the pGMP stage.…”

Section: Discussionmentioning

confidence: 98%

Molecular and cellular effects of oncogene cooperation in a genetically accurate AML mouse model

et al. 2012

View full text Add to dashboard Cite

Biallelic CEBPA mutations and FMS-like tyrosine kinase receptor 3 (FLT3) length mutations are frequently identified in human acute myeloid leukemia (AML) with normal cytogenetics. However, the molecular and cellular mechanisms of oncogene cooperation remain unclear because of a lack of disease models. We have generated an AML mouse model using knockin mouse strains to study cooperation of an internal tandem duplication (ITD) mutation in the Flt3 gene with commonly observed CCAAT/enhancer binding protein alpha (C/EBPa) mutations. This study provides evidence that FLT3 ITD cooperates in leukemogenesis by enhancing the generation of leukemia-initiating granulocyte-monocyte progenitors (GMPs) otherwise prevented by a block in differentiation and skewed lineage priming induced by biallelic C/EBPa mutations. These cellular changes are accompanied by an upregulation of hematopoietic stem cell and STAT5 target genes. By gene expression analysis in premalignant populations, we further show a role of FLT3 ITD in activating genes involved in survival/transformation and chemoresistance. Both multipotent progenitors and GMP cells contain the potential to induce AML similar to corresponding cells in human AML samples showing that this model resembles human disease.

show abstract

“…12,13 Several downstream progenitors with myeloid and/or lymphoid potential continue to express FLT3 whereas megakaryocyte/erythrocyte progenitors do not. 11,[14][15][16][17][18] With the exception of dendritic cells (DC), which retain FLT3 on their surface, FLT3 expression is downregulated as cells undergo myeloid or lymphoid commitment. Deletion of either FLT3 or FLT3L results in defects in the developmental potential of myeloid/lymphoid progenitors underscoring the importance of FLT3 in their development.…”

Section: Introductionmentioning

confidence: 99%

In vivo evidence for an instructive role of fms-like tyrosine kinase-3 (FLT3) ligand in hematopoietic development

et al. 2014

View full text Add to dashboard Cite

© F e r r a t a S t o r t i F o u n d a t i o nshown to be crucial in sustaining adult B-cell lymphopoiesis. 21 However, ablation of the FLT3/FLT3L axis alone did not result in a complete block in the generation of any hematopoietic lineage, suggesting that FLT3L might exert its crucial role in hematopoiesis through interactions with other cytokines, such as interleukin-7 (IL-7) or stem cell factor. 19,22,23 To elucidate the specific action of FLT3L on hematopoiesis in vivo, FLT3L has been administered, with the results confirming the important role of FLT3L in DC generation. 24 We have previously shown that apart from DC, FLT3L injection leads to transient expansion of a FLT3 + progenitor population with lymphoid and myeloid potential. 25 In order to evaluate the role of FLT3L in the development of different hematopoietic lineages, in this study we investigated the effects of sustained over-expression of FLT3L in a transgenic mouse model. Our study confirms the positive role of FLTL in DC development and highlights the importance of this cytokine in the survival and expansion of lymphoid and myeloid progenitors. Furthermore, our data provide evidence for an instructive role of FLT3L in hematopoietic development. Methods MiceAll mice used in this study were bred and maintained in our animal facility under pathogen-free conditions and all animal experiments were performed in accordance with institutional guidelines (permission numbers 1887 and 1888). Immunization to induce a Tdependent antibody response and FLT3L treatment of mice were carried out as previously described. 25 Cell culturesST2, OP9 and OP9 stromal cells expressing Notch ligand Deltalike 1 (OP9DL1) were maintained in IMDM supplemented with 5 x 10 -5 M β-mercaptoethanol, 1 mM glutamine, 0.03% w/v Primatone (Quest Naarden, the Netherlands), 100 U/mL penicillin, 100 μg/mL streptomycin and 5% fetal bovine serum. Co-cultures of stromal cells with sorted progenitor cells were performed as previously described 25 (and Online Supplementary Materials and Methods). Platelet countsBlood was drawn from the tail vein of mice and incubated with 1% ammonium oxalate for 10 min at room temperature. Following incubation, live cells were counted in a Neubauer hemocytometer. ImmunofluorescenceSpleens were snap-frozen and embedded in OCT-compound (Sakura, Zoetermeer, the Netherlands), and 5 μm sections were prepared. Sections were fixed in acetone for 10 min, air-dried for 60 min and subsequently stained with fluorescein isothiocyanatelabeled anti-CD90, phycoerythrin-labeled anti-IgM and allophycocyanin-labeled anti-CD11c antibodies for 30 min. Results Splenomegaly and lymphadenopathy in FLT3L transgenic miceTo investigate the effect of prolonged FLT3L overexpression, we generated mice expressing the human FLT3L gene under the control of the β-actin promoter (hereafter referred to as FLT3L-Tg mice). FLT3L levels in the blood were in the range of 500-1000 ng/mL, as assesed by enzyme-linked immunosorbent assay using an antihuman FLT3L antibody developed in our ...

show abstract

Expression and role of FLT3 in regulation of the earliest stage of normal granulocyte-monocyte progenitor development

Cited by 39 publications

References 40 publications

FLT3 expression initiates in fully multipotent mouse hematopoietic progenitor cells

FLT3 expression initiates in fully multipotent mouse hematopoietic progenitor cells

Molecular and cellular effects of oncogene cooperation in a genetically accurate AML mouse model

In vivo evidence for an instructive role of fms-like tyrosine kinase-3 (FLT3) ligand in hematopoietic development

Contact Info

Product

Resources

About