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Review
. 2017 May 24;18(6):1115.
doi: 10.3390/ijms18061115.

The Cytokine Flt3-Ligand in Normal and Malignant Hematopoiesis

Panagiotis Tsapogas  1 , Ciaran James Mooney  2 , Geoffrey Brown  3   4 , Antonius Rolink  5
Affiliations
Review

The Cytokine Flt3-Ligand in Normal and Malignant Hematopoiesis

Panagiotis Tsapogas et al. Int J Mol Sci. .

Abstract

The cytokine Fms-like tyrosine kinase 3 ligand (FL) is an important regulator of hematopoiesis. Its receptor, Flt3, is expressed on myeloid, lymphoid and dendritic cell progenitors and is considered an important growth and differentiation factor for several hematopoietic lineages. Activating mutations of Flt3 are frequently found in acute myeloid leukemia (AML) patients and associated with a poor clinical prognosis. In the present review we provide an overview of our current knowledge on the role of FL in the generation of blood cell lineages. We examine recent studies on Flt3 expression by hematopoietic stem cells and its potential instructive action at early stages of hematopoiesis. In addition, we review current findings on the role of mutated FLT3 in leukemia and the development of FLT3 inhibitors for therapeutic use to treat AML. The importance of mouse models in elucidating the role of Flt3-ligand in normal and malignant hematopoiesis is discussed.

Keywords: Flt3; Flt3 with internal tandem duplications (FLT3-ITD); acute myeloid leukemia (AML); cytokines; hematopoiesis.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Flt3 expression in murine hematopoietic cells. Flt3 expression in progenitor and mature hematopoietic cells. The fate choices that are available to HSC are a continuum as shown by the short central arc below the yellow arrow. The fates choices of each of the indicated progenitors are shown as a shorter arc that spans the end cell types each progenitor cell population can give rise to. Red circles indicate Flt3 expression by the corresponding cell type. The grey section of the spectrum and grey shading of the MEP and mature cells indicates that these cells do not express Flt3. Progenitor cells that have not been investigated for expression of Flt3 are shown in a faded color. Expression is confined to myeloid and lymphoid progenitors as opposed to megakaryocyte/erythroid progenitors. HSC: Hematopoietic Stem Cell; MPP: Multi-Potent Progenitor; LMPP: Lymphoid-primed Multi-potent Progenitor; MEP: Megakaryocyte-Erythrocyte Progenitor; CMP: Common Myeloid Progenitor; GMP: Granulocyte-Macrophage Progenitor; CLP: Common Lymphoid Progenitor; EPLM: Early Progenitors with Lymphoid and Myeloid potential; ILC: Innate Lymphoid Cell; DC: Dendritic Cell; Eo: Eosinophil; CFU: Colony Forming Unit; Mon: Monocyte; M-CSFR: Macrophage–Colony Stimulating Factor Receptor; EpoR: Erythropoietin Receptor; GM: Granulocyte-Macrophage; ProB: progenitor B-lymphocyte; B: B-lymphocyte; T: T-lymphocyte.
Figure 2
Figure 2
Potential instructive role of FL in early hematopoiesis. (A) Relative percentages of MEP, GMP and CMP populations in wild-type mice (n = 4) injected with 10 μg of FL daily, for a period of 5 days. Cells were pre-gated as Live, Lin−kit+Sca1/CD127− and identified as: MEP: CD16lowCD34−, GMP: CD16+CD34+, CMP: CD16lowCD34+. *: significant (p = 0.017), ns: not significant. FL: Fms-like tyrosine kinase 3 ligand, MEP: Megakaryocyte-Erythrocyte Progenitor, GMP: Granulocyte-Macrophage Progenitor, CMP: Common Lymphoid Progenitor. BM: Bone Marrow. (B) Schematic representation of the proposed model for the instructive action of FL. HSC: Hematopoietic Stem Cell; MPP: Multipotent Progenitor; Ly/Mye Prog: Lymphoid/Myeloid Progenitor; Meg/Ery Prog: Megakaryocyte/Erythrocyte Progenitor; FL: Fms-like tyrosine kinase 3 ligand.
Figure 3
Figure 3
Schematic diagram of the structure of wild-type FLT3 (left) and FLT3-ITD (right) receptors. Ig: Immunoglobulin-like domain; TM: transmembrane domain; JM: juxta-membrane domain; KD: kinase domain; ITD: internal tandem duplications.
See this image and copyright information in PMC

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