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Flk2/Flt3 promotes both myeloid and lymphoid development by expanding non-self-renewing multipotent hematopoietic progenitor cells.

ABSTRACT: Defining differentiation pathways is central to understanding the pathogenesis of hematopoietic disorders, including leukemia. The function of the receptor tyrosine kinase Flk2 (Flt3) in promoting myeloid development remains poorly defined, despite being commonly mutated in acute myeloid leukemia. We investigated the effect of Flk2 deficiency on myelopoiesis, focusing on specification of progenitors between HSC and mature cells. We provide evidence that Flk2 is critical for proliferative expansion of multipotent progenitors that are common precursors for all lymphoid and myeloid lineages, including megakaryocyte/erythroid (MegE) cells. Flk2 deficiency impaired the generation of both lymphoid and myeloid progenitors by abrogating propagation of their common upstream precursor. At steady state, downstream compensatory mechanisms masked the effect of Flk2 deficiency on mature myeloid output, whereas transplantation of purified progenitors revealed impaired generation of all mature lineages. Flk2 deficiency did not affect lineage choice, thus dissociating the role of Flk2 in promoting cell expansion and regulating cell fate. Surprisingly, despite impairing myeloid development, Flk2 deficiency afforded protection against myeloablative insult. This survival advantage was attributed to reduced cell cycling and proliferation of progenitors in Flk2-deficient mice. Our data support the existence of a common Flk2(+) intermediate for all hematopoietic lineages and provide insight into how activating Flk2 mutations promote hematopoietic malignancy by non-Flk2-expressing myeloid cells.

SUBMITTER: Beaudin AE

PROVIDER: S-EPMC4047989 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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Flk2/Flt3 promotes both myeloid and lymphoid development by expanding non-self-renewing multipotent hematopoietic progenitor cells.

Beaudin Anna E AE Boyer Scott W SW Forsberg E Camilla EC

Experimental hematology 20131211 3

Defining differentiation pathways is central to understanding the pathogenesis of hematopoietic disorders, including leukemia. The function of the receptor tyrosine kinase Flk2 (Flt3) in promoting myeloid development remains poorly defined, despite being commonly mutated in acute myeloid leukemia. We investigated the effect of Flk2 deficiency on myelopoiesis, focusing on specification of progenitors between HSC and mature cells. We provide evidence that Flk2 is critical for proliferative expansi ...[more]

PMID: 24333663

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Project description:Interleukin-7 (IL-7) and Flt3-ligand (FL) are two cytokines important for the generation of B cells, as manifested by the impaired B cell development in mice deficient for either cytokine or their respective receptors and by the complete block in B cell differentiation in the absence of both cytokines. IL-7 is an important survival and proliferation factor for B cell progenitors, whereas FL acts on several early developmental stages, prior to B cell commitment. We have generated mice constitutively over-expressing both IL-7 and FL. These double transgenic mice develop splenomegaly and lymphadenopathy characterized by tremendously enlarged lymph nodes even in young animals. Lymphoid, myeloid and dendritic cell numbers are increased compared to mice over-expressing either of the two cytokines alone and the effect on their expansion is synergistic, rather than additive. B cell progenitors, early progenitors with myeloid and lymphoid potential (EPLM), common lymphoid progenitors (CLP) and lineage-, Sca1+, kit+ (LSK) cells are all increased not only in the bone marrow but also in peripheral blood, spleen and even lymph nodes. When transplanted into irradiated wild-type mice, lymph node cells show long-term multilineage reconstitution, further confirming the presence of functional hematopoietic progenitors therein. Our double transgenic mouse model shows that sustained and combined over-expression of IL-7 and FL leads to a massive expansion of most bone marrow hematopoietic progenitors and to their associated presence in peripheral lymphoid organs where they reside and potentially differentiate further, thus leading to the synergistic increase in mature lymphoid and myeloid cell numbers. The present study provides further in vivo evidence for the concerted action of IL-7 and FL on lymphopoiesis and suggests that extramedullary niches, including those in lymph nodes, can support the survival and maintenance of hematopoietic progenitors that under physiological conditions develop exclusively in the bone marrow.

Dataset Information

Flk2/Flt3 promotes both myeloid and lymphoid development by expanding non-self-renewing multipotent hematopoietic progenitor cells.

Publications

Flk2/Flt3 promotes both myeloid and lymphoid development by expanding non-self-renewing multipotent hematopoietic progenitor cells.

Similar Datasets

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