Single-cell gene expression levels show substantial variations among cells in seemingly homogenous populations. Astrocytes perform many control and regulatory functions in the central nervous system. In contrast to neurons, we have limited knowledge about functional diversity of astrocytes and its molecular basis. To study astrocyte heterogeneity and stem/progenitor cell properties of astrocytes, we used single-cell gene expression profiling in primary mouse astrocytes and dissociated mouse neurosphere cells. The transcript number variability for astrocytes showed lognormal features and revealed that cells in primary cultures to a large extent co-express markers of astrocytes and neural stem/progenitor cells. We show how subpopulations of cells can be identified at single-cell level using unsupervised algorithms and that gene correlations can be used to identify differences in activity of important transcriptional pathways. We identified two subpopulations of astrocytes with distinct gene expression profiles. One had an expression profile very similar to that of neurosphere cells, whereas the other showed characteristics of activated astrocytes in vivo.
Dysfunction of T cells and natural killer (NK) cells has been proposed to deter- IntroductionAcute myeloid leukemia (AML) is characterized by a deficiency of hematopoietic progenitor and stem cell development with a resulting accumulation of immature myeloid cells in BM. [1][2][3] The current treatment in AML comprises an initial phase of intensive chemotherapy, induction, and consolidation that aims to achieve and maintain complete remission (CR). 4,5 Younger patients may subsequently undergo allogeneic stem cell transplantation, 6 whereas few therapeutic options are available in the postconsolidation phase for other patients. 7 The occurrence of relapse after CR along with the poor postrelapse survival significantly explains the dismal longterm survival of patients with AML. 4,8 In several studies investigators point to a role for lymphocytes, such as cytotoxic T cells and natural killer (NK) cells, in the surveillance of the malignant clone in AML and in determining prognosis. 9 T cells are considered to mediate the graft-versusleukemia reaction that significantly accounts for the reduced rate of leukemic relapse after allogeneic stem cell transplantation, 10,11 and several tumor-associated antigens of relevance to T-cell reactivity are expressed by AML cells. 12 A role for NK cells in surveillance of AML cells was demonstrated, as exemplified by the favorable outcome when authors used transplants with donor/recipient class I disparities, which facilitates NK cell-mediated destruction of residual leukemic cells. 13 In addition, multiple deficiencies of T-and NK-cell functions, with ensuing relapse risk and poor prognosis, have been observed in patients with AML who did not undergo transplantation. [14][15][16][17][18] In earlier studies, investigators demonstrated that nonmalignant phagocytic cells down-modulate lymphocyte functions by producing and releasing NADPH oxidase-derived reactive oxygen species (ROS). [19][20][21][22][23] These findings have formed the basis for the use of a NADPH oxidase inhibitor in conjunction with IL-2 as a relapsepreventive strategy in patients with AML. 24,25 In this study, we monitored the surface expression of gp91 phox , a component of the ROS-generating NADPH oxidase, 26 on leukemic cells recovered from BM and blood of newly diagnosed patients with AML and explored whether ROS produced by leukemic cells compromise Tand NK-cell function. These analyses were performed with cells recovered from patients with defined morphologic subtypes of AML cells on the basis of French-American-British (FAB) classification. 27 We report that AML cells from patients with monocytic forms of AML (FAB classes M4/M5), but not cells from patients with myeloblastic AML (FAB class M2) or immature AML (FAB class M1), express the NADPH oxidase, produce ROS, and trigger extensive apoptosis in adjacent T and NK cells. Our results are suggestive of a novel mechanism of immune evasion in myelomonocytic and monocytic AML. Methods Sampling of BM and peripheral bloodPeripheral blood or BM from 26 untreated...
In a phase IV trial, 84 patients (age 18–79) with acute myeloid leukemia (AML) in first complete remission (CR) received cycles of immunotherapy with histamine dihydrochloride (HDC) and low-dose human recombinant interleukin 2 (IL-2) for 18 months to prevent leukemic relapse. During cycles, the treatment resulted in expansion of CD56bright (CD3−/16−/56bright) and CD16+ (CD3−/16+/56+) natural killer (NK) cells in the blood along with increased NK cell expression of the natural cytotoxicity receptors (NCRs) NKp30 and NKp46. Multivariate analyses correcting for age and risk group demonstrated that high CD56bright NK cell counts and high expression of NKp30 or NKp46 on CD16+ NK cells independently predicted leukemia-free survival (LFS) and overall survival (OS). Our results suggest that the dynamics of NK cell subsets and their NCR expression may determine the efficiency of relapse-preventive immunotherapy in AML.
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