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Bereshchenko, O.1; Bruscoli, S.2; Frammartino, T.2; Flamini, S.2; Gagliardi, A.2; de Barros, Viana Z.2; Riccardi, C.2

doi: 10.1097/01.HS9.0000560016.74784.7d
Poster Session I: Hematopoiesis, stem cells and microenvironment

1Medicine; Philosophy and social sciences and education

2Medicine, University of Perugia, Perugia, Italy

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Life-long production of blood cells depends on the sustained activity of hematopoietic stem cells (HSC). The maintenance of HSC is linked to their quiescent state, while activation of HSC proliferation is normally associated with differentiation into a more lineage restricted progenitors and a loss of long-term stem cell potential. The balance between HSC proliferation and quiescence is tightly regulated by intrinsic and extrinsic cues in the bone marrow. This regulatory network may become altered by various stresses, leading to aberrant HSC cell cycling, loss of HSC function, and hematological malignancy. Endogenous glucocorticoid hormones (GC) influence the proliferation homing of HSC via regulation of CXCL12-CXCR4 axis. Moreover, pharmacologic doses of synthetic GC induce apoptosis in lymphocytes as well as early lymphoid progenitors. However, the effect of GC on survival, proliferation and lineage commitment of the most primitive HSCs are not yet defined.

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GILZ (Glucocorticoid-Induced Leucine Zipper) is a gene rapidly induced by GC that mediates some of its effects, including regulation of cell growth and differentiation. We have found that gilz mRNA is expressed in HSC and progenitor cells (HPC) and is dowregulated in myeloid progenitor cells.

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We have addressed the role of GILZ in HSC homeostasis using GILZ knock-out (KO) mice.

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Under steady state, young GILZ-KO mice show a significant decrease in HSC and an increase in HPC frequency, while the number of HSC remains unchanged. Competitive repopulation studies using WT and GILZ-KO bone marrows cells (CD45.2+) along with WT helper cells (CD45.1+) revealed a significant decrease in the frequency of GILZ-KO compared to WT CD45.2+ cells in the peripheral blood, suggesting that GILZ-deficient HSCs have competitive disadvantage compared to WT cells. Consistently, the number of HSC was significantly decreased in the bone marrows of GILZ-KO transplanted mice, suggesting that GILZ is required for the proper control of the HCS number in the bone marrow. To demonstrate that the lack of GILZ is associated with decreased HSC function, we have performed 5-FU treatment experiments in mice transplanted with WT or GILZ KO bone marrow cells to ensure the hematopoietic cell intrinsic effect of GILZ deletion on mice survival. Mice bearing GILZ KO hematopoietic cells showed significantly earlier mortality caused by the 5-FU treatment. To dissect the mechanism of the defect in HSC function upon GILZ deletion, we performed comprehensive RNAseq analysis of gene expression in WT and GILZ KO HSCs. We identified several deregulated cellular pathways implicated in HSC function.

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Overall, these data identify GILZ is a novel critical regulator of HSCs function.

Copyright © 2019 The Authors. Published by Wolters Kluwer Health Inc., on behalf of the European Hematology Association.