This work identifies MALAT1 as a requisite downstream effector of oncogenic feedforward inflammatory circuits necessary for the development of TET2-mutated CH and fulminant myeloid malignancy. We elucidate a novel mechanism by which MALAT1 "shields" p65 from dephosphorylation to potentiate this circuit and nominate MALAT1 inhibition as a future therapeutic strategy.
©2024 American Association for Cancer Research.

Acute radiation syndrome (ARS) manifests after exposure to high doses of radiation in the instances of radiologic accidents or incidents. Facilitating regeneration of the bone marrow (BM), namely the hematopoietic stem and progenitor cells (HSPCs), is key in mitigating ARS and multi-organ failure. JNJ-26366821, a PEGylated thrombopoietin mimetic (TPOm) peptide, has been shown as an effective medical countermeasure (MCM) to treat hematopoietic-ARS (H-ARS) in mice. However, the activity of TPOm on regulating BM vascular and stromal niches to support HSPC regeneration has yet to be elucidated.
C57BL/6J mice (9-14 weeks old) received sublethal or lethal total body irradiation (TBI), a model for H-ARS, by 137Cs or X-rays. At 24 h post-irradiation, mice were subcutaneously injected with a single dose of TPOm (0.3 mg/kg or 1.0 mg/kg) or PBS (vehicle). At homeostasis and on days 4, 7, 10, 14, 18, and 21 post-TBI with and without TPOm treatment, BM was harvested for histology, BM flow cytometry of HSPCs, endothelial (EC) and mesenchymal stromal cells (MSC), and whole-mount confocal microscopy. For survival, irradiated mice were monitored and weighed for 30 days. Lastly, BM triple negative cells (TNC; CD45-, TER-119-, CD31-) were sorted for single-cell RNA-sequencing to examine transcriptomics after TBI with or without TPOm treatment.
At homeostasis, TPOm expanded the number of circulating platelets and HSPCs, ECs, and MSCs in the BM. Following sublethal TBI, TPOm improved BM architecture and promoted recovery of HSPCs, ECs, and MSCs. Furthermore, TPOm elevated VEGF-C levels in normal and irradiated mice. Following lethal irradiation, mice improved body weight recovery and 30-day survival when treated with TPOm after 137Cs and X-ray exposure. Additionally, TPOm reduced vascular dilation and permeability. Finally, single-cell RNA-seq analysis indicated that TPOm increased the expression of collagens in MSCs to enhance their interaction with other progenitors in BM and upregulated the regeneration pathway in MSCs.
TPOm interacts with BM vascular and stromal niches to locally support hematopoietic reconstitution and systemically improve survival in mice after TBI. Therefore, this work warrants the development of TPOm as a potent radiation MCM for the treatment of ARS.
© 2024. The Author(s).

Background: Acute radiation syndrome (ARS) manifests after exposure to high doses of radiation in the instances of radiologic accidents or incidents. Facilitating the regeneration of the bone marrow (BM), namely the hematopoietic stem and progenitor cells (HSPCs), is a key in mitigating ARS and multi-organ failure. JNJ-26366821, a PEGylated thrombopoietin mimetic (TPOm) peptide, has been shown as an effective medical countermeasure (MCM) to treat hematopoietic-ARS (H-ARS) in mice. However, the activity of TPOm on regulating BM vascular and stromal niches to support HSPC regeneration has not yet been elucidated. Methods C57BL/6J mice (9–14 weeks old) received sublethal or lethal total body irradiation (TBI), a model for H-ARS, by 137 Cs or X-rays. At 24 hours post-irradiation, mice were subcutaneously injected with a single dose of TPOm (0.3 mg/kg or 1.0 mg/kg) or PBS (vehicle). At homeostasis and on days 4, 7, 10, 14, 18, and 21 post-TBI with and without TPOm treatment, BM was harvested for histology, BM flow cytometry of HSPCs, endothelial (EC) and mesenchymal stromal cells (MSC), and whole-mount confocal microscopy. For survival, irradiated mice were monitored and weighed for 30 days. Lastly, BM triple negative cells (TNC; CD45 − , TER-119 − , CD31 − ) were sorted for single-cell RNA-sequencing to examine transcriptomics after TBI with or without TPOm treatment. Results At homeostasis, TPOm expanded the number of circulating platelets and HSPCs, ECs, and MSCs in the BM. Following sublethal TBI, TPOm improved BM architecture and promoted recovery of HSPCs, ECs, and MSCs. Furthermore, TPOm elevated VEGF-C levels in normal and irradiated mice. Following lethal irradiation, mice improved body weight recovery and 30-day survival when treated with TPOm after 137 Cs and X-ray exposure. Additionally, TPOm reduced vascular dilation and permeability. Finally, single-cell RNA-seq analysis indicated that TPOm increased the expression of collagens in MSCs to enhance their interaction with other progenitors in BM and upregulated the regeneration pathway in MSCs. Conclusions TPOm interacts with BM vascular and stromal niches to locally support hematopoietic reconstitution and systemically improve survival in mice after TBI. Therefore, this work warrants the development of TPOm as a potent radiation MCM for the treatment of ARS.

Ionizing radiations (IR) alter hematopoietic stem cell (HSC) function on the long term, but the mechanisms underlying these effects are still poorly understood. We recently showed that IR induces the derepression of L1Md, the mouse young subfamilies of LINE-1/L1 retroelements. L1 contributes to gene regulatory networks. However, how L1Md are derepressed and impact HSC gene expression are not known. Here, we show that IR triggers genome-wide H3K9me3 decrease that occurs mainly at L1Md. Loss of H3K9me3 at intronic L1Md harboring NF-κB binding sites motifs but not at promoters is associated with the repression of HSC-specific genes. This is correlated with reduced NFKB1 repressor expression. TNF-α treatment rescued all these effects and prevented IR-induced HSC loss of function in vivo. This TNF-α/NF-κB/H3K9me3/L1Md axis might be important to maintain HSCs while allowing expression of immune genes during myeloid regeneration or damage-induced bone marrow ablation.
© 2022 Pelinski et al.

Ambient fine particulate matter (PM) serves an important role in the development of cardiovascular disease, including atherosclerosis. Antioxidant N‑acetyl cysteine (NAC) has protective effects in the cardiovascular system. However, it is unknown if NAC prevents PM‑potentiated atherosclerosis in hyperlipidemia. Low‑density lipoprotein (LDL) receptor knockout mice were pretreated with 1 mg/ml NAC in drinking water for 1 week and continued to receive NAC, high‑fat diet and intranasal instillation of PM for 1 week or 6 months. Blood plasma was collected for lipid profile, oxidized (ox‑)LDL, blood reactive oxygen species (ROS) and inflammatory cytokine (TNF‑α, IL‑1β and IL‑6) measurement. Blood cells were harvested for endothelial progenitor cell (EPC) population and intracellular ROS analysis. Murine aorta was isolated for atherosclerotic plaque ratio calculation. NAC treatment maintained circulating EPC level and significantly decreased blood ox‑LDL and ROS, inflammatory cytokines, mononuclear and EPC intracellular ROS levels as well as aortic plaque ratio. NAC prevented PM‑potentiated atherosclerosis by inhibiting plasma ROS‑induced ox‑LDL elevation, mononuclear cell and EPC intracellular ROS‑induced circulating EPC reduction and inflammatory cytokine production.