The bone marrow (BM) niche comprises multiple cell types that regulate hematopoietic stem/progenitor cell (HSPC) migration out of the niche and into the circulation. Here, we demonstrate that osteocytes, the major cellular component of mature bone, are regulators of HSPC egress. Granulocyte colony-stimulating factor (G-CSF), used clinically to mobilize HSPCs, induces changes in the morphology and gene expression of the osteocytic network that precedes changes in osteoblasts. This rapid response is likely under control of the sympathetic nervous system, since osteocytes express the β2-adrenergic receptor and surgical sympathectomy prevents it. Mice with targeted ablation of osteocytes or a disrupted osteocyte network have comparable numbers of HSPCs in the BM but fail to mobilize HSPCs in response to G-CSF. Taken together, these results indicate that the BM/bone niche interface is critically controlled from inside of the bone matrix and establish an important physiological role for skeletal tissues in hematopoietic function.

Osteocytes act as mechanosensors to control local bone volume. However, their roles in the homeostasis of remote organs are largely unknown. We show that ablation of osteocytes in mice (osteocyte-less [OL] mice) leads to severe lymphopenia, due to lack of lymphoid-supporting stroma in both the bone marrow and thymus, and complete loss of white adipose tissues. These effects were reversed when osteocytes were replenished within the bone. In contrast, neither in vivo supply of T cell progenitors and humoral factors via shared circulation with a normal parabiotic partner nor ablation of specific hypothalamic nuclei rescued thymic atrophy and fat loss in OL mice. Furthermore, ablation of the hypothalamus in OL mice led to hepatic steatosis, which was rescued by parabiosis with normal mice. Our results define a role for osteocytes as critical regulators of lymphopoiesis and fat metabolism and suggest that bone acts as a central regulator of multiple organs.

We performed a systematic review of data from nine clinical trials of WT1 peptide vaccination in patients with myelodysplastic syndromes and/or acute myeloid leukemia (MDS/AML), published between 2004 and 2012. A total of 51 patients were eligible for analysis. Vaccination with WT1 peptides proved safe and feasible in patients with MDS/AML, in studies from different institutions. Additionally, clinical responses and clinical benefit were observed, with some patients achieving and maintaining remission long-term (more than 8 years). A significant correlation between induction of WT1-specific T cells and normalization/reduction of WT1 mRNA levels and progression-free survival was noted in a number of studies. However, larger studies are warranted to confirm these results. Interestingly, the majority of trials reported the presence of WT1-specific T cells with limited or absent functionality prior to vaccination, which increased in frequency and function after vaccination. In conclusion, WT1 peptide vaccination strategies were safe in this heterogeneous group of patient with MDS/AML. Larger and more homogeneous studies or randomized clinical trials are needed to quantify the contribution of WT1 peptide vaccines to clinical responses and long-term survival.

Posttranscriptional machinery regulates inflammation and is associated with autoimmunity as well as tumorigenesis in collaboration with transcription factors. We previously identified the tumor suppressor gene transformed follicular lymphoma (TFL) on 6q25 in a patient with follicular lymphoma, which transformed into diffuse large B cell lymphoma. TFL families have a common RNase domain that governs macrophage-mediated inflammation. In human peripheral blood, TFL is dominantly expressed at the glycine- and tryptophan-rich cytoplasmic processing bodies of T lymphocytes, and it is persistently upregulated in activated T cells. To address its physiological role, we established TFL−/− mice in which TFL−/− lymphocytes proliferated more rapidly than TFL+/+ upon stimulation with inappropriate cytokine secretion, including IL-2, IL-6, and IL-10. Moreover, TFL inhibited the synthesis of cytokines such as IL-2, IL-6, IL-10, TNF-α, and IL-17a by 3′ untranslated region RNA degradation. Experimental autoimmune encephalitis induced in TFL−/− mice demonstrated persistent severe paralysis. CNS-infiltrated CD4+ T cells in TFL−/− mice contained a higher proportion of Th17 cells than did those in TFL+/+ mice during the resolution phase, and IL-17a mRNA levels were markedly increased in TFL−/− cells. These results suggest that TFL may play an important role in attenuating local inflammation by suppressing the infiltration of Th17 cells in the CNS during the resolution phase of experimental autoimmune encephalitis. TFL is a novel gradual and persistent posttranscriptional regulator, and the TFL-driven attenuation of excessive inflammation could contribute to recovery from T cell–mediated autoimmune diseases.