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Inside Experimental Hematology July and August 2014

Posted By Connections Editor, Friday, September 05, 2014
Updated: Wednesday, September 03, 2014

Inside this issue July 2014

Phenotypic characterization of the erythroid island macrophages that mediate the block of medullary erytrhropoiesis by G-CSF

See Jacobsen et al., pages 547561.

In the bone marrow (BM), as well as in the spleen and liver, macrophages are the central component of erythroblastic islands, which are specialized niches within which definitive mammalian erythroblasts proliferate and differentiate. In these islands, the central macrophage extends cytoplasmic protrusions to a ring of surrounding erythroblasts. It has been proposed that early in erythroid maturation, the macrophages provide nutrients and proliferative and survival signals to the erythroblasts, and phagocytose extrudes erythroblast nuclei at the conclusion of erythroid maturation. This group and others have previously demonstrated that G-CSF mediates the mobilization of hematopoietic stem cells (HSCs) from the BM via the suppression of BM macrophages. Due to the key role of macrophages in erythropoiesis, in this study, Jacobsen et al. investigated the effect of G-CSF in red blood cell formation and characterized the phenotype of the macrophages involved. They report that G-CSF blocks erythropoiesis in mouse BM but not in the spleen or liver, via the depletion of medullar erythroid island macrophages. These macrophages express F4/80, VCAM-1, ER-HR3, CD169, and Ly-6G antigens. This precise identification of the phenotype of the erythropoietic island macrophages should facilitate future studies of these cells in steady-state and disease, which until now have been hampered by the lack of specific markers.

Signaling via TLR9 augments production of human NK-like cells

See Vadillo et al., pages 562573.

It is well known that the hematopoietic system can respond to different types of insults by favoring the production of particular cell types. In keeping with this, it has been shown that pathogens and their products can influence blood cell production in a Toll-like receptor (TLR)-dependent manner. For example, lymphopoiesis is suppressed in herpes simplex–infected mice, whereas dendritic cells are preferentially made from progenitor cells that reside within bone marrow. However, the vast majority of such studies focused on the myeloid arm of hematopoiesis, and they were conducted with experimental animals. Thus, much remains to be learned about lymphoid, and particularly natural killer (NK) cell production in humans. In this issue, Vadillo et al. demonstrate that ligation of the TLR9 stimulates adult human lymphoid progenitors to divide and generate NK-like cells. Interestingly, this phenomenon—marked by elevated expression of IL-15Rβ—was observed in adult, but not neonatal cells. These findings accord with previous reports concerning ontogeny-related changes in human lymphocyte production and raise interesting questions. Are neonates threatened by infections because they lack the ability to boost innate immunity? Alternatively, NK progenitors may have already been exposed to endogenous TLR ligands and sterile inflammatory processes in utero. Related to that issue, do the neonatal versus adult differences represent residual maternal/fetal tolerance processes? It is clear that we need to better understand immune system development within the context of endogenous and pathogen-derived TLR ligands.

Lmo2 has epigenetic effects on CD4 in T-cell leukemia

See Cleveland et al., pages 581–593.

LIM domain Only-2 (Lmo2) is one of the most frequently deregulated oncogenes in human T-cell acute lymphoblastic leukemia (T-ALL). This group and others have found that prior to the onset of leukemia, Lmo2 overexpression causes an arrest in the differentiation sequence of T-cell progenitor cells before the onset of expression of CD4 and CD8. In this paper, Cleveland et al. discovered a mouse T-ALL cell line derived from CD2-Lmo2 transgenic mice that has an unusual differentiation block. The cell line, 32080, is clonal but has cells with negative, intermediate, and high CD4 expression, whereas CD8 expression is homogeneous. Pure CD4− or CD4+ populations were sorted but the expression of CD4 was unstable since the sorted cells acquired CD4 or lost CD4 after replication. The CD4+CD8+ population resembled the double positive (DP) cells of normal T-cell differentiation and the CD4−CD8+ population resembled the intermediate single positive (ISP) T-cell progenitors. Similar to their normal counterparts, the DP-like population had a higher baseline rate of apoptosis and increased sensitivity to dexamethasone. This variegated pattern of CD4 expression in 32080 cells was regulated by Lmo2, Notch1, Runx1, and histone deacetylation. The 32080 cell line provides a unique model of ISP to DP developmental stage transition, where the CD4 gene is known to be epigenetically regulated, and also suggests unique epigenetic effects of the Lmo2 oncogene.

Inside this Issue August 2014

Editorial for the Special Issue on Genomics and Model Organisms: New Horizons for Experimental Hematology

A comment from the Editor-in-Chief, Dr. Keith Humphries, pages 595-597

On behalf of the journal, I am very pleased to introduce a special issue devoted to two exciting research topics of growing importance to our field—Genomics, guest edited by Dr. Bertie Gottgens, and Model Organisms, guest edited by Dr. David Traver. This combined series of reviews highlights recent advances across the wide range of model organisms and genome-scale approaches with a particular emphasis on strategies that are showing promise for extracting new biological insights relevant to normal hematopoiesis and disease. In the following, Drs. Gottgens and Traver provide a glimpse of the topics covered in their respective review series that I hope will encourage a deep read and discussion.

A special note of thanks to the many authors who so enthusiastically and kindly agreed to contribute to this review series.

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