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first step was the process of screening a variety of leukemia samples for mutations in the coding region of approximately 2000 genes associated with cancer signaling, including all kinases. This screening showed CSF3R mutations in 16 of 27 patients with CNL and atypical CML (59%); by contrast, the mutation was rare in patients with AML (1 of 92) and other leukemias. Next, samples with the CSF3R mutation were tested in vitro with chemical kinase inhibitors and small interfering RNA directed against kinases known to be activated by normal CSF3R.8 These studies suggested that different types of CSF3R mutations had differential sensitivity to different therapeutic agents. Frameshift or nonsense mutations that truncated the cytoplasmic tail of CSF3R appeared to deregulate and activate its downstream signaling partners SRC kinase and TNK2 kinase (and thus were sensitive to the multikinase inhibitor dasatinib). Membrane proximal mutations appeared to cause ligand-independent activation of the downstream effector JAK2 and thus were susceptible to the JAK inhibitor ruxolitinib. The authors confirmed the transforming potential and differential drug sensitivity using in vitro colony-forming assays. Finally, the authors treated a patient whose leukemia harbored a CSF3R proximal membrane mutation. As predicted from these studies, the patient had a response to the JAK inhibitor ruxolitinib, with dramatic decreases in white-cell, neutrophil, and platelet counts. In addition to the obvious therapeutic benefit in these rare disorders, this study is important in a broader sense. It shows the power of genetic screening to uncover new potential drug targets and provide a rationale for using drugs that are already available for other indications. Notably, the association between the CSF3R mutation and CNL and atypical CML was found in a large sequencing of the usual suspects of cancer signaling. Skeptics often deride large-scale screening studies as fishing expeditions, although these

are actually an excellent idea if the object is to catch fish. Furthermore, the work went from identification of the CSF3R mutation, through in vitro studies, to a successful clinical application without a murine model. Thus, this study bucks the common notion that one cannot learn anything of significance without engineering a mouse that nature itself could not create. E. Donnall Thomas, winner (with Joseph E. Murray) of the Nobel Prize in Physiology or Medicine in 1990 for his pioneering work on allogeneic transplantation, often said that medical science did work not by giant breakthroughs but by small, calculated steps. This study shows the potential power of studying a small problem very craftily and is an example of what genetically informed treatment may look like in the near future. This is how we will beat cancer, one gene, one disease at a time.
Disclosure forms provided by the author are available with the full text of this article at NEJM.org. From the Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle.
1. Druker BJ, Guilhot F, OBrien SG, et al. Five-year follow-up

of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 2006;355:2408-17. 2. Levine RL, Wadleigh M, Cools J, et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell 2005;7:387-97. 3. Maxson JE, Gotlib J, Pollyea DA, et al. Oncogenic CSF3R mutations in chronic neutrophilic leukemia and atypical CML. N Engl J Med 2013;368:1781-90. 4. Beekman R, Touw IP. G-CSF and its receptor in myeloid malignancy. Blood 2010;115:5131-6. 5. Beekman R, Valkhof MG, Sanders MA, et al. Sequential gain of mutations in severe congenital neutropenia progressing to acute myeloid leukemia. Blood 2012;119:5071-7. 6. Hernndez JM, del Caizo MC, Cuneo A, et al. Clinical, hematological and cytogenetic characteristics of atypical chronic myeloid leukemia. Ann Oncol 2000;11:441-4. 7. Bhm J, Schaefer HE. Chronic neutrophilic leukaemia: 14 new cases of an uncommon myeloproliferative disease. J Clin Pathol 2002;55:862-4. 8. Tyner JW, Yang WF, Bankhead A III, et al. Kinase pathway dependence in primary human leukemias determined by rapid inhibitor screening. Cancer Res 2013;73:285-96.
DOI: 10.1056/NEJMe1302363
Copyright 2013 Massachusetts Medical Society.

Early-Life Wheezing and Respiratory Syncytial Virus Prevention


Robert F. Lemanske, Jr., M.D. Wheezing illnesses in preschool children have treatment, and prognosis with regard to the perplexed clinicians for decades in terms of their subsequent development of asthma. Although differential diagnosis, short-term and long-term wheezing illnesses have been described in more
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than 50% of preschool children, many eventually outgrow this problem.1 A major concern with using wheezing to define an illness is the subjectivity involved in assessing this symptom in terms of caregiver recognition, agreement between parental and physician assessment, and recognition of the degree of severity that portends subsequent administration of systemic glucocorticoids or hospitalization.2 Nonetheless, because more objective pulmonary-function studies are difficult to perform in the majority of preschool children, wheezing has been used as a surrogate marker to identify clinically relevant lower-airway obstruction. Viral respiratory tract illnesses, particularly those due to infection with respiratory syncytial virus (RSV)3 or human rhinovirus (HRV),4 have frequently been associated with the development of persistent wheezing, childhood asthma, or both. These findings suggest that the prevention of infection with either virus has the potential to reduce the risk of either or both of these outcomes. On the basis of these relationships, it seems plausible that currently available anti-RSV therapy could reduce the risk of recurrent wheezing secondary to RSV infection. Using a retrospective and nonrandomized study design, Simes et al. treated premature infants with palivizumab and compared them with an untreated cohort matched for chronologic and gestational age. During a 24-month follow-up period, physiciandiagnosed recurrent wheezing was significantly less frequent in the treated group.5 This reduction in wheezing frequency was seen only in children who did not have a family history of atopy.6 In this issue of the Journal, Blanken and colleagues extend these observations in a randomized, double-blind, placebo-controlled trial using the total number of wheezing days in the first year of life as the primary outcome.7 Remarkably, premature infants treated with palivizumab had a significant 61% relative decrease in the total number of wheezing days during the first year of life. Moreover, the effect of RSV prevention on the number of wheezing days persisted in the post-prophylaxis period (i.e., starting at 2 months after the last injection). As anticipated, palivizumab treatment reduced hospitalizations related to RSV infection; in addition, treatment had a significant effect on reducing rates of medically attended nonhospitalized RSV infection.
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Given the limitations inherent in using wheezing as a primary outcome measure discussed previously, these data show rather convincingly that palivizumab treatment can reduce both RSV infection rates and subsequent recurrent wheezing in preterm infants. These relationships were noted despite rather low rates of parental procurement of nasopharyngeal-swab samples (29%) and respiratory pathogen detection (60%) during wheezing episodes. However, study coordinator and investigator oversight of the trial was excellent, with more than 90% of scheduled injections completed in both the placebo and palivizumab groups. With the potentially strong association between early-life wheezing and the development of childhood asthma, what do these data mean in terms of predicting future asthma risk in this population of high-risk infants? Two of the most important risk factors for asthma in children are the presence of allergic sensitization8 and wheezing during viral4 or perhaps bacterial9 respiratory tract illnesses in the first few years of life. Recent data from the Childhood Origins of Asthma birth cohort study suggest that allergic sensitization may be causative in the subsequent development of virus-induced wheezing.10 One proposed mechanistic pathway to explain these sequential relationships involves the impairment of innate responses to viral pathogens owing to the cross-linking of IgE receptors, which results in increased airway inflammation and the subsequent loss of lung function in sensitized persons.11 It is important to recognize, however, that other asthma-risk pathways, which are independent of allergic sensitization, may also contribute to increased asthma risk. One such pathway may involve genetic variation at the 17q21 locus and virus-induced wheezing illnesses. In a recent study, variants at this locus were associated with HRV wheezing illnesses in early life but not with RSV wheezing illnesses. The associations of 17q21 variants with asthma were restricted to children who previously had HRV wheezing illnesses, resulting in a significant interaction effect with respect to asthma risk. These associations were independent of the presence or absence of allergic sensitization.12 In the current study, the effect of RSV prevention with palivizumab on the total number of wheezing days was similar regardless of pa-

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editorials

rental history of atopy. As stated previously, Simes et al.6 found that palivizumab reduced wheezing only in children without a family history of atopy. The fact that a genetic background of atopy did not influence wheezing frequency in either study suggests that palivizumab treatment, while decreasing morbidity in infancy, may have limited effects on at least some asthmarisk pathways. Whether more definitive evaluations of allergic sensitization (i.e., allergen-specific IgE testing) and 17q21 locus variation or treatment of term infants would alter these findings, improve risk predictions, or influence the natural history of asthma warrants further study.
Disclosure forms provided by the author are available with the full text of this article at NEJM.org. From the Departments of Pediatrics and Medicine, University of Wisconsin School of Medicine and Public Health, Madison.
1. Martinez FD, Wright AL, Taussig LM, et al. Asthma and

4. Jackson DJ, Gangnon RE, Evans MD, et al. Wheezing rhino-

2. Skytt N, Bnnelykke K, Bisgaard H. To wheeze or not to

wheezing in the first six years of life. N Engl J Med 1995;332:133-8.

wheeze: that is not the question. J Allergy Clin Immunol 2012; 130(2):403.e5-407.e5. 3. Wu P, Hartert TV. Evidence for a causal relationship between respiratory syncytial virus infection and asthma. Expert Rev Anti Infect Ther 2011;9:731-45.

virus illnesses in early life predict asthma development in highrisk children. Am J Respir Crit Care Med 2008;178:667-72. 5. Simes EA, Groothuis JR, Carbonell-Estrany X, et al. Paliviz umab prophylaxis, respiratory syncytial virus, and subsequent recurrent wheezing. J Pediatr 2007;151:34-42. 6. Simes EA, Carbonell-Estrany X, Rieger CH, et al. The effect of respiratory syncytial virus on subsequent recurrent wheezing in atopic and nonatopic children. J Allergy Clin Immunol 2010;126:256-62. 7. Blanken MO, Rovers MM, Molenaar JM, et al. Respiratory syncytial virus and recurrent wheeze in healthy preterm infants. N Engl J Med 2013;368:1791-9. 8. Sly PD, Boner AL, Bjrksten B, et al. Early identification of atopy in the prediction of persistent asthma in children. Lancet 2008;372:1100-6. 9. Bisgaard H, Hermansen MN, Bnnelykke K, et al. Association of bacteria and viruses with wheezy episodes in young children: prospective birth cohort study. BMJ 2010;341:c4978. 10. Jackson DJ, Evans MD, Gangnon RE, et al. Evidence for a causal relationship between allergic sensitization and rhinovirus wheezing in early life. Am J Respir Crit Care Med 2012;185: 281-5. 11. Durrani SR, Montville DJ, Pratt AS, et al. Innate immune responses to rhinovirus are reduced by the high-affinity IgE receptor in allergic asthmatic children. J Allergy Clin Immunol 2012;130:489-95. 12. aliskan M, Bochkov YA, Kreiner-Mller E, et al. Rhinovirus wheezing illness and genetic risk of childhood-onset asthma. N Engl J Med 2013;368:1398-407.
DOI: 10.1056/NEJMe1302063
Copyright 2013 Massachusetts Medical Society.

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