Between Bedside and Bench

  • Between Bedside and Bench |

    Macrophages are responsive to local tissue signals and alter their phenotypes accordingly. In disease tissues this means that macrophage phenotypes may change with disease progression, exacerbating or facilitating the resolution of the pathology.

    • Kate Liddiard
    •  & Philip R Taylor
  • Between Bedside and Bench |

    Targeted genome editing by engineered endonucleases allows the precise introduction of gene deletions and substitutions into the target genome. In 'Bench to Bedside', Keith Joung and his colleagues discuss how genome-editing technologies could be applied to engineer disease-associated somatic variation into human cell lines and disease models. This would allow the functional interpretation of such variants, which could then be applied to molecular diagnostics in the clinic. In 'Bedside to Bench', Angelo Lombardo and Luigi Naldini consider the potential applications of genome editing in the clinic, in which engineered endonucleases have been shown to be safe. Endonucleases could replace disease-associated genes with wild-type versions or be used to delete genes encoding receptors essential to viral host entry to prevent infection.

    • Angelo Lombardo
    •  & Luigi Naldini
  • Between Bedside and Bench |

    Oxidative stress has long been linked to disease development and accelerated aging, prompting professionals in the biomedical field to suggest the use of antioxidants to prevent or even reverse these conditions. But growing clinical evidence is showing that this in fact might not be effective, calling for additional investigation to prove that certain molecular factors involved in oxidation, specifically reactive oxidative species (ROS), are not detrimental. In “Bedside to Bench,” Michael Ristow highlights recent human studies with antioxidant supplementation that have failed to show any improvement in health span. Moreover, other relevant evidence has pointed towards a beneficial role for ROS in lifespan under stress conditions, although how this is mediated and regulated inside the cell is not fully understood. In “Bench to Bedside,” Hiroyuki Kawagishi and Toren Finkel peruse the biological and signaling underpinnings of ROS in living organisms, which suggest different amounts of ROS may explain their dual role in lifespan and disease and the lack of effect of antioxidants in the body. The authors propose targeting pathways and molecules involved in removing cellular damage rather than ROS, which could make therapies to increase lifespan more effective and preclude diseases caused by oxidation and aging.

    • Michael Ristow
  • Between Bedside and Bench |

    The development of new therapies is an arduous, time-consuming and costly task. Furthermore, the development of many compounds runs into issues related to safety. Drug repurposing, where drugs with established safety in humans are tested and developed for efficacy in a disease other than the one for which they were developed, is gaining traction because of its potential to overcome an initial bottleneck in the drug development process. In “Bedside to Bench,” Stephen Strittmatter discusses the types of scenario in which drug repurposing may be of benefit, such as when a drug is repurposed for a new molecular target or for the same target in a different disease. In “Bench to Bedside,” Michael Pollak focuses on a recent study that suggest that biguanides that are normally used in the treatment of diabetes could have direct cyotoxic action on cancer cells with mutations in respiratory complex I. The pharmacokinetic hurdles that may need to be overcome for this to be translated to the clinic are also discussed.

    • Stephen M Strittmatter
  • Between Bedside and Bench |

    The challenges posed by the biology of the virus remain a barrier to obtaining a complete cure using current antivirals and to developing a working vaccine that will protect from infection and clear disease. Researchers are keenly working to uncover how to elicit long-term broadly neutralizing antibody responses in humans that will protect against infection from all HIV clades and to ensure that people already infected will also have a chance at clearing the virus and being cured. In “Bedside to Bench,” Florian Klein and Henning Gruell discuss a recent study that tracked how broadly neutralizing antibodies developed in an HIV-infected individual during the natural course of the disease. The findings will help create a roadmap to identify the necessary steps to induce antibody maturation for achieving a broad and potent protective humoral response. Another important aspect that defies HIV eradication in infected individuals is the existence of viral reservoirs that allow the virus to hide from antiviral killing. In “Bench to Bedside,” Robert Siliciano peruses recent advances in animal models providing evidence that eliciting effector memory cellular responses to HIV may help eradicate—or prevent the establishment of—latent reservoirs. This strategy could contribute to clearing HIV in treated infected individuals and add to the protection of a humoral vaccine response.

    • Henning Gruell
    •  & Florian Klein
  • Between Bedside and Bench |

    Certain biological features are inherent traits of cancer, yet some of them still hold mysteries for researchers and clinicians. The heterogeneity of a tumor mass is an old concept that has lately become both a puzzling factor and a feature that should be harnessed to better understand tumor vulnerabilities. Improved scientific approaches to further determine and uncover the meaning of these heterogeneous features are still needed to translate findings into ways to develop therapies, identify drug response biomarkers and stratify patients. In Bedside to Bench, Maria Kleppe and Ross L. Levine look at recent clinical cancer trials that have advanced the field and discuss main questions regarding the role of tumor heterogeneity in predicting therapeutic response and tumor progression. In addition, they raise awareness of the relevance of the interactions among different tumor entities and their contribution to the malignancy of the whole tumor. In Bench to Bedside, Kornelia Polyak peruses studies that uncover specific mutations conferring endocrine drug resistance in breast tumors and that add to our knowledge of the evolution and architecture of tumors, and she discusses how this can be used to implement drug regimens.

    • Maria Kleppe
    •  & Ross L Levine
  • Between Bedside and Bench |

    Despite the existence of numerous antibiotics, recurrence of certain infections, such as those caused by Clostridium difficile, remains a clinical challenge. The root of the problem is the detrimental effect of antibiotics on the function and composition of intestinal commensals. To tackle C. difficile refractoriness to treatment and infection recurrence, scientists are trying to understand how a healthy microbiota may keep this pathogen at bay to identify the microbial contributors of protection and to develop targeted probiotic-based therapies. In 'Bedside to Bench', Ying Taur and Eric Pamer discuss the potential of fecal microbiota transplantation (FMT) and peruse mechanisms to explain its efficacy. Alteration of bile salts, which are involved in germination of C. difficile spores, by the healthy microbiota may explain why microbiome depletion upon antibiotic treatment can lead to pathogen overgrowth. In 'Bench to Bedside', Ruth Ley peruses a recent study suggesting that sialic acids increasingly released by gut commensals after antibiotic treatment may play a crucial part in boosting C. difficile growth. Starving the pathogen of this carbohydrate in the gut by FMT or, more specifically, with engineered probiotics that can outcompete the pathogen for sialic acids may prove effective to treat or even prevent C. difficile infection.

    • Ying Taur
    •  & Eric G Pamer
  • Between Bedside and Bench |

    Metabolic regulators that permit adaptation to changes in caloric intake have been shown to be needed to protect from age-related disorders. Sirtuins play a crucial part in this program, impinging on not only aging but also other diseases. New findings are uncovering the multifaceted activity of sirtuins in living organisms and their effects on healthspan. In 'Bedside to Bench', Leonard Guarente discusses how different sirtuins are hindering cancer metabolism through suppression of the Warburg effect. The apparent antitumor effects of several sirtuins through their regulation of different metabolic pathways suggest therapeutic approaches to induce sirtuin function or that of downstream targets may block cancer growth. In 'Bench to Bedside', Eric Verdin peruses a few studies in different animal models showing that increased amounts of nicotinamide adenine dinucleotide (NAD), a cofactor of sirtuins, may have a positive effect in longevity and span of healthy life, or healthspan, by increasing sirtuin enzymatic activity. Whether harnessing NAD therapeutically is a potential way to extend lifespan and ameliorate diseases is still open to debate.

    • Leonard Guarente
  • Between Bedside and Bench |

    Although stem cells were initially thought to be the magic bullet for numerous diseases, translation of a stem cell–based cure into the clinic is still a work in progress. Basic research is shedding light into the potential of stem cells, and different research fronts are now exploring how to exploit this potential to tackle diverse conditions. In 'Bench to Bedside', Akemi Tanaka, Mark Sauer, Dieter Egli and Daniel Kort discuss how genome transfer from eggs of mothers with mutated mitochondria into an enucleated egg from a healthy female donor at an early developmental stage can eliminate mitochondrial disease. The negligible mutant mitochondrial DNA carryover and the differentiation of subsequent embryonic stem cells into various cell types with healthy mitochondrial DNA content suggest this could be used to prevent transmission of mitochondrial disease to the offspring. The authors discuss safety concerns and remaining technical questions that need to be resolved to make way for this new technology in the clinic. In 'Bedside to Bench', Nan Yang and Marius Wernig peruse a small study of children with a myelin disorder showing that transplantation of human neural stem cells leads to engraftment and donor cell–derived myelination.

    • Akemi J Tanaka
    • , Mark V Sauer
    • , Dieter Egli
    •  & Daniel H Kort
  • Between Bedside and Bench |

    Given the multisystemic nature of the metabolic syndrome, the field is now aiming at perusing both intrinsic and environmental factors from a biological and therapeutic standpoint. Physicians often advise obese individuals suffering from type 2 diabetes to lose weight through exercise and healthy diets. Although it may be an obvious recommendation, a large study has recently shown that weight loss achieved through these lifestyle changes does not significantly reduce cardiovascular disease events in these patients compared to conventional diabetes care. In 'Bedside to Bench', Julie A. Lovshin and Daniel J. Drucker discuss the limitations of this study, the conclusions that can be drawn regarding the true benefit of weight loss in this context and the molecular factors that deserve further attention at the bench in light of this trial. In 'Bench to Bedside', Eleftheria Maratos-Flier examines the role of antidiabetic drugs in both host and gut microbiota metabolism. These effects in the intestinal flora support advocating an increase in our understanding of how the gut microbiome affects obesity for finding the means to harness its therapeutic potential.

    • Julie A Lovshin
    •  & Daniel J Drucker
  • Between Bedside and Bench |

    The field of tumor immunology has been flooded with exciting therapeutic advances on many fronts. Immunotherapies targeting T cell inhibitory molecules have proven highly effective in some cancers, but additional strategies to induce tumor immunity, such as cancer vaccination, could further increase tumor killing. The combination of both will probably be the way forward in future immunotherapy. In 'Bedside to Bench', Robert Vonderheide and Katherine Nathanson discuss the potential of cancer genomics to identify specific tumor mutations in patients that may be used as targets in cancer vaccines to overcome problems linked to self-antigen epitopes used nowadays. Despite the existing biological and technical hurdles, a framework to implement personalized cancer vaccines in the clinic may be worth considering. In 'Bench to Bedside', Glenn Dranoff peruses the clinical efficacy and detrimental effects of two T cell immune-checkpoint inhibitors, alone and in combination, in patients with melanoma. The studies underscore the need to continue investigating specific tumor events directly involving tumor evasion to develop combinatorial strategies that will reduce drug-related pathology while achieving anti-tumor efficacy.

    • Robert H Vonderheide
    •  & Katherine L Nathanson
  • Between Bedside and Bench |

    How eosinophils function in different tissues during health and disease is not completely understood. On the one hand, they seem to be crucial in inflammatory disorders, which suggests that pathways related to their activation and regulation may be potential therapeutic targets. In asthma, the role of these cells is well known; however, airway inflammation owing to increased eosinophils in lung tissue in nonallergic asthma has only recently started to be in the limelight. In 'Bedside to Bench', Guy G. Brusselle, Tania Maes and Ken R. Bracke peruse the disease pathway triggering eosinophilic inflammation in nonallergic eosinophilic asthma and the potential targets that may lead to effective therapies. The authors also discuss a clinical study that highlights the need to phenotype patients using cellular and molecular markers to improve treatment responses. However, on the other hand, a recent study has also shown a homeostatic role of eosinophils in metabolism in fat tissue. In 'Bench to Bedside', Clare M. Lloyd and Sejal Saglani examine evidence that hints at the crucial role of the location of eosinophils in different tissues such as lung, where they cause inflammation, and visceral fat, where they improve glucose homeostasis. Clinical data that correlate lung tissue eosinophilia with obesity may spur new research to shed light on the role of these inflammatory cells in obese individuals with asthma and on how to improve treatments in these patients.

    • Clare M Lloyd
    •  & Sejal Saglani
  • Between Bedside and Bench |

    Discerning which mediators drive pathogenesis in chronic inflammatory diseases can be complex: immune cells can release various pathogenic cytokines, and numerous cytokines may either cause one specific disease or many. Human validation and mechanistic studies will be necessary to identify the key immune cells and cytokines for a given inflammatory disorder and to pinpoint which cytokine might be the appropriate target for tackling each disease. In 'Bedside to Bench', Georg Schett et al. discuss how human trials targeting different cytokines suggest the existence of a hierarchical framework of cytokines that defines groups of chronic inflamatory diseases rather differently from the homogenous molecular disease pattern previously assumed. In 'Bench to Bedside', Vijay Kuchroo and Dominique Baeten peruse the role of interleukin-17A as drug target in several autoimmune diseases to highlight how success in the clinic will need understanding of pathogenic pathways and the immunological and tissue context of each inflammatory disease.

    • Georg Schett
    • , Dirk Elewaut
    • , Iain B. McInnes
    • , Jean-Michel Dayer
    •  & Markus F. Neurath
  • Between Bedside and Bench |

    Using brain surgery, specific areas in the brain can be stimulated with electrical impulses to reversibly change their activity and alleviate symptoms related to mental illnesses. This so-called deep brain stimulation and other methodological advances that even more selectively activate specific groups of neurons can give us clues as to what neural circuitry is involved in a particular mental disorder and whether therapeutic activation of these brain areas and neurons may be effective. In 'Bedside to Bench', Eric Nestler discusses two trials of individuals with anorexia nervosa in which deep brain stimulation of different brain areas resulted in improvement of behavioral domains associated with the syndrome. The results and potential of this technique in animals and humans may bring us closer to understanding the neurobiology of anorexia nervosa, which still remains a mystery and poses a challenge for treatment. In 'Bench to Bedside', Jennifer Warner-Schmidt peruses recent findings that uncover the functional connectivity of brain regions involved in depression and how activation of cortical regions can result in antidepressant effects that can compensate for the malfunction of other brain circuits that results in depression.

    • Eric J Nestler
  • Between Bedside and Bench |

    Myocardial infarction can cause irreversible heart muscle cell damage and lingering cardiac problems that can eventually lead to heart failure. For over a decade, researchers have been trying to coax stem cells to differentiate into cardiomyocytes to repair damaged heart tissue, with limited success. In 'Bedside to Bench', Christine L. Mummery and Richard T. Lee lay out a framework for re-evaluating cardiac cell therapies in the context of two recent clinical trials, in which autologous cardiac stem cells derived from heart biopsies were transferred into patients, with promising, albeit difficult to interpret, results. Results from previous clinical trials using autologous bone marrow–derived adult stem cells to induce cardiac regeneration add to the debate about how to cautiously move forward in the cardiac regeneration field and to the questions that need to be urgently answered at the bench. In 'Bench to Bedside', Young-Jae Nam, Kunhua Song and Eric N. Olson discuss a number of recent studies in rodents showing that cardiac fibroblasts can be reprogrammed, via miRNAs and a transcription factor 'cocktail', to express cardiac genes, which resulted in improved cardiac function in the animals, suggesting a new way forward for fixing damaged heart tissue.

    • Christine L Mummery
    •  & Richard T Lee
  • Between Bedside and Bench |

    Cancer resistance to targeted therapies seems to be a field of active research. But there are still open questions as to what drives drug resistance not only in metastatic tumor cells but also in disseminated tumor cells (DTCs) during adjuvant treatment, before metastases are established in other organs. Targeting this residual cancer disease or keeping these DTCs in a dormant state may be a way to stop progression to metastatic disease. For this, a further understanding of the biology of these cells is necessary. In 'Bedside to Bench', Bernhard Polzer and Christopher Klein put forward several scenarios to explain the different resistant mechanisms that might account for DTCs unresponsiveness to cancer drugs and emphasize the relevance of synchronizing targeted therapies with the changing responsive or dormant state of disseminated cancer cells in the clinic. In 'Bench to Bedside', Julio A Aguirre-Ghiso, Paloma Bragado and Maria Soledad Sosa discuss possible cell-intrinsic and microenvironment-derived signaling pathways that may be exploited to maintain dormancy in DTCs and explore the possibility of using dormancy gene signatures to identify individuals with dormant disease.

    • Bernhard Polzer
    •  & Christoph A Klein
  • Between Bedside and Bench |

    Modern medicine keeps unraveling new ways to investigate autoimmunity, leading to the production of boundless amounts of genetic, cellular and imaging data. Although the precision with which this information can define the etiology and mechanisms of a particular autoimmune disease is encouraging, much work lies ahead until all the knowledge acquired can be translated into the clinic. In 'Bedside to Bench', Calliope A. Dendrou, John I. Bell and Lars Fugger discuss the promises and limitations of genome-wide and next-generation genetic studies to provide further understanding of mechanisms driving autoimmune disorders and the role of experimental medicine in the new era of integrative clinical practice and personalized medicine. In 'Bench to Bedside', Lawrence Steinman argues the concept of a 'hub and spoke' pattern of T cell activation and organ targeting in multiple sclerosis, inflammatory bowel disease and type 1 diabetes. This paradigm suggests new ways to develop drugs to keep autoreactive T cells in the organ where activation occurs and preclude them from reaching the target organ and cause disease.

    • Calliope A Dendrou
    • , John I Bell
    •  & Lars Fugger
  • Between Bedside and Bench |

    Despite the irrefutable role of inflammation in psoriasis, a complete knowledge of what immune cells and cytokines are involved during initiation and progression of this skin disease is lacking. Moreover, the complexities of the immune cell network and potential differences between mice and humans have led to translational failures. It is therefore important that we acquire in-depth understanding of what inflammatory players, of the many involved, are crucial, if we wish to develop effective therapies. In 'Bedside to Bench', James Krueger discusses how a subset of T cells, TH17 cells, which release interleukin-17 in humans, seem to be essential for pathogenesis of psoriasis. The interplay between interleukin-17 and other cytokines that may potentially be involved in psoriasis also needs further investigation. Additionally, there are open questions as to what subset of T cells, other than TH17, also produce interleukin-17 and when. In 'Bench to Bedside', Burkhard Becher and Stanislav Pantelyushin examine this issue by looking at a mouse model of skin inflammation that resembles psoriasis in humans. A class of skin-invading innate immune cells called γδ T cells was shown to drive skin inflammation in this model, particularly during the early stages of the disease, suggesting that innate immunity plays an important part in the initiation of psoriasis.

    • Burkhard Becher
    •  & Stanislav Pantelyushin
  • Between Bedside and Bench |

    There is increasing interest in understanding how epilepsy initiates and how to thwart the establishment of the disease. Many questions remain open as to what targets may the best for preventing epilepsy and whether any common triggering pathway exists to treat this complex malady. In 'Bedside to Bench', Rod C. Scott and Gregory Holmes discuss alternative therapies to treat neonatal seizures to prevent chronic cognitive impairment and brain developmental problems, which can lead to epilepsy later in life. Increasing inhibitory signals in the developing brain may be useful in dampening brain hyperexcitability—and enhanced susceptibility for seizures—and blocking epilepsy development in children. In 'Bench to Bedside', Annamaria Vezzani argues how the mTOR pathway may be a potential target for blocking epileptogenesis. The role of mTOR in seizures in early life and progression of established disease raises the possibility that mTOR could be a common mediator involved in epilepsy at different stages of disease initiation and progression. Given the lack of current antiepileptic drugs to prevent seizures in children and to block epileptogenesis, developing new disease-modifying therapies remains a priority.

    • Rod C Scott
    •  & Gregory L Holmes
  • Between Bedside and Bench |

    Influenza viruses can cause a broad spectrum of disease severity, including devastating cases in some people. Several factors influence the epidemiological success of the virus; the mechanisms of transmission and the strategies for prevention and treatment have an impact on the disease outcome and the incidence of flu infection in the population. Understanding how and why the viruses spread so efficiently among people and determining possible ways to harness this transmission have been arduous tasks, given the limitations of flu animal models. In 'Bedside to Bench', Kanta Subbarao and Seema S. Lakdawala peruse a study that used a human challenge model to assess influenza transmission; this experimental approach shows how transmission can be studied in humans and emphasizes factors that are different compared to animals, such as distinct disease severity and incidence. Lessons can be taken to optimize animal studies. Another issue that dictates the severity of flu episodes is the potential emergence of drug-resistant strains in treated individuals. In 'Bench to Bedside', Anne Kelso and Aeron C. Hurt discuss another concern—the presence of drug-resistant viruses with additional permissive mutations that make them fit to infect and compete with wild-type strains. The fact that these strains can be found in untreated people and can spread poses a public health concern and a challenge for scientists to find new drugs and assess antiviral combinations.

    • Seema S Lakdawala
    •  & Kanta Subbarao
  • Between Bedside and Bench |

    Formation of plaques in artery walls, or atherogenesis, is known to lead to cardiovascular disease risk and heart disease. Low-density lipoproteins (LDLs), which deliver cholesterol to inflammatory cells in blood vessels, are linked to disease, which is commonly managed using cholesterol-lowering therapies. Whether increasing levels of high-density lipoproteins (HDLs), which remove cholesterol from the circulation, can be cardioprotective has not been clear, despite early clinical studies showing evidence for a positive effect in cardiovascular disease. In 'Bench to Bedside', Daniel J. Rader and Alan R. Tall discuss how the field should focus on promoting reverse cholesterol transport that would result in cholesterol efflux from macrophages to biliary excretion rather than simply trying to increase HDL cholesterol levels. Understanding how different molecular mechanisms operate in this 'HDL flux hypothesis' will uncover ways to develop HDL-targeted therapeutics that will protect from cardiovascular and heart disease. In 'Bedside to Bench', Jay W. Heinecke peruses clinical studies to propose better and simpler ways to measure reverse cholesterol transport in the clinic. Genetic alterations and factors involved in HDL functionality may be useful for quantifying HDL function and finding effective drugs to lower cardiovascular disease risk.

    • Daniel J Rader
    •  & Alan R Tall
  • Between Bedside and Bench |

    Millions of healthy bacteria colonize our guts from the moment we are born. Changes in the composition and abundance of these commensals affect the entire immune system and can predispose us to a variety of diseases, including intestinal infections, inflammatory and metabolic diseases, and cancer. The gut microbiome interacts not only with the host mucosa but also with potential pathogens; understanding what interactions and pathways are crucial for maintaining homeostasis and protecting the host from harmful bacteria and diseases can open new avenues to developing gut microbiota–based therapeutic approaches. In 'Bench to Bedside', Michael R. Howitt and Wendy S. Garrett examine the importance of metabolic crosstalk between the microbiota and the host in human metabolism and the development of cardiovascular disease. This adds one more layer of complexity to understanding what contributes to this pathology and how to harness the microbiota and their metabolic pathways to prevent it. In 'Bedside to Bench', Nobuhiko Kamada, Grace Chen and Gabriel Núñez discuss how targeting interactions between commensals and bacteria causing intestinal disease can lead to effective therapies to control these infections, which currently seem to lack an adequate treatment. Unraveling how commensals help the host prevent or block colonization of these pathogens can suggest new ways to increase our armamentarium to deal with these sometimes deadly intestinal infections.

    • Michael R Howitt
    •  & Wendy S Garrett
  • Between Bedside and Bench |

    Several decades of scientific observations followed by years of basic and now clinical research support the notion that the metabolic power of tumor cells can provide the long-desired Achilles' heel of cancer. Yet many questions remain as to what defines the true metabolic makeup of a tumor and whether well-known factors and pathways involved in metabolic signaling act as tumor suppressors or oncogenes. In 'Bedside to Bench', Kıvanç Birsoy, David M. Sabatini and Richard Possemato discuss how retrospective studies of diabetic individuals with pancreatic cancer treated with the antidiabetic drug metformin point to a possible anticancer effect for this drug. Further research will need to discern whether this drug acts at the organismal level or by directly targeting the power plant of tumor cells. In 'Bench to Bedside', Regina M. Young and M. Celeste Simon peruse the complex function of a key metabolic factor that mediates the cell's response to low oxygen levels, often found in tumors. This hypoxia-inducible factor (HIF) comes in two flavors, which can be either tumor promoting or tumor suppressive, depending on the type of cancer. Because of this, the therapeutic use of HIF inhibitors must proceed with caution. Further defining the relationship between metabolic regulation of HIF and tumor progression may open up new diagnostic tools and treatments.

    • Kıvanç Birsoy
    • , David M Sabatini
    •  & Richard Possemato
  • Between Bedside and Bench |

    The bone marrow niche keeps puzzling scientists in cancer and regenerative medicine. What elements constitute the niche and how it affects neighbor cells in different disease contexts remain to be a matter of debate and extensive investigation. The translational use of hematopoietic stem cells (HSCs) in transplantation biology poses a challenge, given the propensity of these cells to remain quiescent. Although the niche is a good candidate to exploit for reprogramming HSCs and controlling their expansion, new studies have added to its complexity. In 'Bench to Bedside', Paul S. Frenette and Yuya Kunisaki examine these studies to discuss how new players and their signals are involved in HSC maintenance and what the implications are for the development of HSC-based therapies. Among the alterations occurring in leukemias, metabolic events seem to foster cancer progression but may also be involved in cancer predisposition. Rushdia Z. Yusuf, Ying-Hua Wang and David T. Scadden peruse recent clinical and experimental studies that look at myelodysplastic syndromes and secondary leukemias and argue how metabolic changes in these cancers may not only be cell autonomous but also can emanate from the bone marrow stroma. Targeting this niche may open new avenues to reduce the risk for secondary leukemias in cancer survivors.

    • Yuya Kunisaki
    •  & Paul S Frenette