Mutations in Neutrophils and monocytesNeutrophils (also known as "polymorphonuclear leukocytes" and "granulocytes") are terminally differentiated cellular components of the innate immune system that constitute about 35% to 75% of the population of peripheral leukocytes. 1 They kill bacterial and fungal pathogens through phagocytosis and are armed with an arsenal of proteases, antimicrobial peptides, and reactive oxygen species. 2 They also participate in the inflammatory response and produce cytokines, eicosanoids, and other signaling molecules. 3 Monocytes, constituting about 5% to 10% of peripheral leukocytes, are the circulating progenitors of tissue macrophages and dendritic cells and arise in the bone marrow from common myeloid progenitors shared with neutrophils. 4 "Neutropenia" refers to a deficiency in numbers of neutrophils. The normal neutrophil count fluctuates and varies across human populations and within individuals in response to stress and infection but typically well exceeds 1500/L 5 , and neutropenia is usually categorized as severe when the cell count is below 500/L. Common causes of neutropenia include cancer chemotherapy, autoimmune diseases, drug reactions, and hereditary disorders. 6 Among the latter, neutropenia may occur as one component of a number of inherited syndromes diversely featuring morphologic abnormalities of neutrophils, immunodeficiency, involvement of other lineages or pancytopenia, metabolic abnormalities, and systemic findings. This review, however, focuses on the 2 primary genetic forms of neutropenia: cyclic neutropenia (also known as "cyclic hematopoiesis") and the Kostmann syndrome of infantile agranulocytosis, more commonly referred to as "severe congenital neutropenia" (SCN), where mutations of the ELA2 gene, encoding the neutrophil granule serine protease, neutrophil elastase (NE), have proved to be the nearly exclusive or most common cause, respectively. Cyclic neutropeniaIn cyclic neutropenia, the peripheral-blood neutrophil and monocyte counts oscillate in opposite phase to one another with an average 21-day frequency. 6 Peak neutrophil counts tend toward somewhat subnormal values, although they can also be in the normal range. Infections, including aphthous stomatitis, periodontitis, and typhlitis, can arise during the nadir of the cycle, when the neutrophil count drops below 500/L and approaches zero. The infectious flora may differ from what is encountered with acquired neutropenia, suggesting a functional deficiency in neutrophils extending beyond that of low numbers. Cyclic neutropenia is transmitted by autosomal dominant genetics but, as with other often lethal dominant disorders, sporadic cases commonly arise from new germ line mutations. In a remarkable anecdote, a girl with the disease served as a hematopoietic stem cell donor for her sister, who did not have cyclic neutropenia but who was rather suffering from acute lymphoblastic leukemia 7 ; the bone marrow transplantation cured the sibling of leukemia, but it transferred cyclic hematopoiesis to her, ...

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BackgroundThe Gail model is widely used for the assessment of risk of invasive breast cancer based on recognized clinical risk factors. In recent years, a substantial number of single-nucleotide polymorphisms (SNPs) associated with breast cancer risk have been identified. However, it remains unclear how to effectively integrate clinical and genetic risk factors for risk assessment.MethodsSeven SNPs associated with breast cancer risk were selected from the literature and genotyped in white non-Hispanic women in a nested case–control cohort of 1664 case patients and 1636 control subjects within the Women’s Health Initiative Clinical Trial. SNP risk scores were computed based on previously published odds ratios assuming a multiplicative model. Combined risk scores were calculated by multiplying Gail risk estimates by the SNP risk scores. The independence of Gail risk and SNP risk was evaluated by logistic regression. Calibration of relative risks was evaluated using the Hosmer–Lemeshow test. The performance of the combined risk scores was evaluated using receiver operating characteristic curves. The net reclassification improvement (NRI) was used to assess improvement in classification of women into low (<1.5%), intermediate (1.5%–2%), and high (>2%) categories of 5-year risk. All tests of statistical significance were two-sided.ResultsThe SNP risk score was nearly independent of Gail risk. There was good agreement between predicted and observed SNP relative risks. In the analysis for receiver operating characteristic curves, the combined risk score was more discriminating, with area under the curve of 0.594 compared with area under the curve of 0.557 for Gail risk alone (P < .001). Classification also improved for 5.6% of case patients and 2.9% of control subjects, showing an NRI value of 0.085 (P = 1.0 × 10−5). Focusing on women with intermediate Gail risk resulted in an improved NRI of 0.195 (P = 8.6 × 10−5).ConclusionsCombining validated common genetic risk factors with clinical risk factors resulted in modest improvement in classification of breast cancer risks in white non-Hispanic postmenopausal women. Classification performance was further improved by focusing on women at intermediate risk.

To explore the use of stem/progenitor cells from peripheral blood (PB) for allogeneic transplantation, we have studied the mobilization of progenitor cells in normal donors by growth factors. Normal subjects were administered either granulocyte-macrophage colony-stimulating factor (GM-CSF) at 10 micrograms/kg/d, or G-CSF at 10 micrograms/kg/d, or a combination of G- and GM-CSF at 5 micrograms/kg/d each, administered subcutaneously for 4 days, followed by leukapheresis on day 5. Mononuclear cells expressing CD34 (CD34+ cells) were selectively enriched by affinity labeling using Dynal paramagnetic microspheres (Baxter Isolex; Baxter Healthcare Corp, Santa Ana, CA). The baseline CD34+ cells in peripheral blood before mobilization was 0.07% +/- 0.05% (1.6 +/- 0.7/microL; n = 18). On the fifth day after stimulation (24 hours after the fourth dose), the CD34+ cells were 0.99% +/- 0.40% (61 +/- 14/microL) for the 8 subjects treated with G-CSF, 0.25% +/- 0.25% (3 +/- 3/microL, both P < .01 v G-CSF) for the 5 subjects administered GM-CSF, and for the 5 subjects treated with G- and GM-CSF, 0.65% +/- 0.28% (41 +/- 18/microL, P < .5 v GM-CSF). Parallel to this increase in CD34+ cells, clonogenic assays showed a corresponding increase in CFU- GM and BFU-E. The total number of CD34+ cells collected from the G-CSF group during a 3-hour apheresis was 119 +/- 65 x 10(6) and was not significantly different from that collected from the group treated with G- and GM-CSF (101 +/- 35 x 10(6) cells), but both were greater than that from the group treated with GM-CSF (12.6 +/- 6.1 x 10(6); P < .01 for both comparisons). Analysis of the CD34+ subsets showed that a significantly higher percentage of cells with the CD34+/CD38- phenotype is found after mobilization with G- and GM-CSF. In the G-CSF group, immunomagnetic selection of CD34+ cells permitted the enrichment of the CD34+ cells in the apheresis product to 81% +/- 11%, with a 48% +/- 12% yield and to a purity of 77% +/- 21% with a 51% +/- 15% recovery in the G- and GM-CSF group. T cells were depleted from a mean of 4.5 +/- 2.0 x 10(9) to 4.3 +/- 5.2 x 10(6) after selection, representing 99.9% depletion. We conclude that it is feasible to collect sufficient numbers of PB progenitor cells from normal donors with one to two leukapheresis procedures for allogeneic transplantation.(ABSTRACT TRUNCATED AT 250 WORDS)

Although somatic mutations in a number of genes have been associated with development of human tumors, such as lipomas, relatively few examples exist of germline mutations in these genes. Here we describe an 8-year-old boy who has a de novo pericentric inversion of chromosome 12, with breakpoints at p11.22 and q14.3, and a phenotype including extreme somatic overgrowth, advanced endochondral bone and dental ages, a cerebellar tumor, and multiple lipomas. His chromosomal inversion was found to truncate HMGA2, a gene that encodes an architectural factor involved in the etiology of many benign mesenchymal tumors and that maps to the 12q14.3 breakpoint. Similar truncations of murine Hmga2 in transgenic mice result in somatic overgrowth and, in particular, increased abundance of fat and lipomas, features strikingly similar to those observed in the child. This represents the first report of a constitutional rearrangement affecting HMGA2 and demonstrates the role of this gene in human growth and development. Systematic genetic analysis and clinical studies of this child may offer unique insights into the role of HMGA2 in adipogenesis, osteogenesis, and general growth control.