Research articles

Resting CD4⁺ T cells are resistant to HIV-1 infection, but the underlying reasons for this lack of permissiveness have not been clear. Oliver Fackler and colleagues now report that SAMHD1, the deoxynucleoside triphosphate triphosphohydrolase responsible for restriction of HIV-1 infection in myeloid cells, also restricts infection of resting CD4⁺ T cells. The findings shed new light on the mechanisms of cellular and molecular regulation of HIV-1 infection.

Doxorubicin, which induces tumor cell death through effects on topoisomerase-II, is a commonly used chemotherapeutic agent but has the substantial drawback of causing cardiotoxicity. Edward T.H.Yeh and his colleagues now show that doxorubicin-induced cardiotoxicity in mice is due to the deleterious effects of doxorubicin on topoisomerase-IIβ in cardiomyocytes, leading to alterations in gene expression, mitochondrial dysfunction and cell death.

Obesity is often marked by chronic, low-grade inflammation, which is believed to contribute to metabolic disturbances associated with this condition. Chih-Hao Lee and colleagues show that injection of a known immunomodulatory glycan, one found in mother's milk and in S. mansoni egg extract, results in improved metabolic function of the adipose tissue and liver in a mouse dietary-mediated obesity model.

A minority of HIV-1–infected individuals develop broadly neutralizing antibodies, which are considered an important goal of many HIV vaccine strategies. Moore et al. now report their study of the evolution of a broadly neutralizing antibody response targeting a glycan on the viral envelope in two HIV-1–infected individuals. Their findings show that the targeted glycan is absent early in acute infection but develops over time as the virus escapes initial antibody-mediated pressure.

The authors uncover a new mechanism for the regulation of the activity of leukemia-initiating cells in T-ALL. A subpopulation of stem cells with low amounts of reactive oxygen species (ROS) is enriched in their ability to reconstitute disease in mouse models, and this effect is regulated by repression of PKC-θ, which increases ROS production. Moreover, oncogenic NOTCH, a common T-ALL–driving alteration, regulates stem cell activity by increasing RUNX3 expression, which represses RUNX1, a PCK-θ activator, a pathway that is conserved in human patients.

The chromatin-modifying protein SIRT6 has previously been shown to have anti-aging properties. Sundaresan et al. now show that SIRT6 expression is low in failing human hearts and SIRT6 in mice protects the heart by suppressing the activity of the c-Jun transcription factor, which acts as a global regulator of genes encoding components of the IGF-Akt signaling pathway.

The self renewal of hematopoietic stem cells is regulated by the bone marrow microenvironment. Whereas previous studies have focused on the role of osteoblasts, Ingrid Winkler et al. now show that bone marrow endothelial cells in the so-called 'vascular niche' contribute to this regulation by directly inducing HSC proliferation. In mice, deficiency or antagonism of the endothelial-specific adhesion protein E-selectin promotes HSC quiescence and self renewal. These findings may point to a new treatment strategy for preserving HSC function in patients undergoing chemotherapy.

Anaplastic large cell lymphomas (ALCL) often express the oncoprotein NPM-ALK. This study shows that the activator protein 1 family members JUN and JUNB promote lymphoma development through platelet-derived growth factor receptor-β (PDGFRB). Inhibition of PDGFRB prolonged survival of NPM-ALK transgenic mice and increased the efficacy of an ALK-specific inhibitor against transplanted NPM-ALK tumors. Inhibition of PDGFR in a patient with ALCL also resulted in rapid, complete and sustained remission.

House dust promotes allergic responses to inhaled allergens, but it remains unclear what microbial components in dust are required for this activity. Donald N. Cook and his colleagues show that the bacterial protein flagellin stimulates allergic airway responses, and its receptor, Toll-like receptor 5, is required to elicit airway eosinophilia and hyperreactivity in response to dust. Individuals with asthma have higher serum antibody titers to flagellin, suggesting exposure to flagellin is associated with allergic airway disease.

Angiogenesis is induced in response to central nervous system (CNS) injury and inflammation. Toshihide Yamashita and colleagues show that in a mouse model of multiple sclerosis, new vessels form around inflammatory lesions and promote neuronal remodeling, rewiring of the corticospinal tract, and recovery of motor function in these mice. Prostacyclin is released from these vessels and promotes neuronal outgrowth by signaling through the IP receptor on neurons.

Chronic obstructive pulmonary disease (COPD) is now known to be a heterogeneous disorder, hence the pressing need to develop imaging biomarkers to differentiate between the broad range of COPD phenotypes–all of which require different treatments. Here, Craig Galban and his colleagues have adapted the parametric response map technique for the voxel-by-voxel classification analysis of CT lung images taken from a national COPD trial, providing a more objective characterization of the phenotypic contributions of functional small airways disease and emphysema in COPD.

Human T cell function declines with age, reducing the ability of vaccines to protect the elderly against infectious disease. In this issue, Jörg Goronzy and his colleagues shed light on the mechanism by which naive CD4⁺ T cell responses are impaired in elderly individuals. The researchers show that miR-181a is reduced in these cells in older individuals. This results in increased expression of DUSP6, a phosphatase that dampens ERK signaling, which is necessary for optimal T cell receptor sensitivity to antigen.

Spinal and bulbar musclar atrophy (SBMA) is caused by expanded polyglutamine repeats in the androgen receptor, leading to motor neuron degeneration. Gen Sobue and his colleagues describe a molecular cascade whereby mutant androgen receptor upregulates CGRP in neuronal cells, promoting JNK activation and degeneration. The 5-HT1B/1D receptor agonist naratriptan, which is approved for the treatment of migraine, decreases CGRP expression and improves motor performance in a mouse model of SBMA, suggesting a novel therapeutic strategy for SBMA.

Individuals with hemophilia A lack the coagulation factor FVIII and are treated with frequent intravenous injections of FVIII agents. However, many individuals develop antibodies to FVIII and can no longer be treated by FVIII injection. Takehisa Kitazawa and his colleagues report the development of a bispecific antibody to FIXa and FX that mimics the function of FVIII. This antibody reduces bleeding in a nonhuman primate model of hemophilia A, is resistant to the inhibitory effects of FVIII-specific antibodies and has a long half-life after subcutaneous injection.

In congenital neutropenia, myeloid-lineage differentiation in response to the cytokine G-CSF is defective. Julia Skokowa et al. now show that an interplay among three proteins—the adapter proteins HCLS1 and HAX1 and the transcription factor LEF-1—is required for G-CSF–triggered granulocytic differentiation, and they provide evidence that this pathway is dysregulated in both congenital neutropenia and acute myeloid leukemia.

By exploiting the relationship between the transcription factor MYC and the transferrin receptor, where the level of transferrin receptor 1 expression may indicate activation of the MYC oncogenic pathway, Jason Holland and his colleagues have developed a novel PET radiotracer to quantitatively and noninvasively measure MYC activity. The ⁸⁹Zr-desferrioxamine transferrin PET radiotracer was tested in several murine models of inflammation and MYC-driven prostate cancer.

The authors identify LIFR as a breast cancer metastasis suppressor by showing how its loss promotes metastasis without substantial effect on primary tumor growth. This function of LIFR involves promoting the membrane localization of Scribble and enabling the cytoplasmic sequestration of Hippo pathway transducers, thus involving this signaling pathway in metastasis control. LIFR loss is also observed in human breast tumors, where it correlates with poor prognosis.

A limitation of photodynamic therapy (PDT) is the depth of penetration of visible light needed for activation of the photosensitizers, restricting treatment to tumors on or just under the skin’s surface or those lining internal organs and cavities. Niagara Muhammad Idris and colleagues have addressed this issue by developing upconversion fluorescent nanoparticles (UNCs) that convert deeper penetrating near-infrared light to visible wavelengths without sacrificing efficacy for singlet oxygen (1O2) production. The group tested the UNCs in vivo in a subcutaneous mouse tumor model using a dual-sensitizer approach for greater PDT efficacy.

NRAS-driven melanomas have limited therapeutic options. Combining genetically engineered models and oncogenic signaling inhibitors with rational systems-biology approaches, the authors compare the effects of genetic extinction of NRAS to that of chemical pathway inhibition targeting downstream MEK. The differences provide actionable targets by revealing that NRAS signaling operates as a gated output and that MEK inhibition, although inducing apoptosis, is not able to achieve further inhibition of NRAS-induced outputs such as cell-cycle progression. A combination of MEK and CDK4 inhibitors provides a more complete inhibition of NRAS signaling and a more effective antitumor effect in vivo.

Although type I phosphatidylinositol 3-kinases (PI3Ks) are well studied signaling proteins, the functions of other PI3Ks are more enigmatic. Kazuaki Yoshioka et al. find that the type II PI3K-2α isoform regulates endosomal trafficking and cell signaling in endothelial cells. Angiogenic and vascular permeability responses are attenuated in mice lacking PI3K-2α, pointing to this enzyme as a potential target for treating vascular disease.