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      Ascorbate regulates haematopoietic stem cell function and leukaemogenesis

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          Abstract

          Stem cell fate can be influenced by metabolite levels in culture but it is unknown whether physiological variations in metabolite levels in normal tissues regulate stem cell function in vivo. We developed a metabolomics method for analysis of rare cell populations isolated directly from tissues and used it to compare haematopoietic stem cells (HSCs) to restricted haematopoietic progenitors. Each haematopoietic cell type had a distinct metabolic signature. Human and mouse HSCs had unusually high levels of ascorbate, which declined with differentiation. Systemic ascorbate depletion in mice increased HSC frequency and function, partly by reducing Tet2 function, a dioxygenase tumor suppressor. Ascorbate depletion cooperated with Flt3 ITD leukaemic mutations to accelerate leukaemogenesis, though cell-autonomous and possibly non-cell-autonomous mechanisms, in a manner that was reversed by dietary ascorbate. Ascorbate acted cell-autonomously to negatively regulate HSC function and myelopoiesis through Tet2-dependent and Tet2-independent mechanisms. Ascorbate thus accumulates within HSCs to promote Tet function in vivo, limiting HSC frequency and suppressing leukaemogenesis.

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          Prognostic relevance of integrated genetic profiling in acute myeloid leukemia.

          Acute myeloid leukemia (AML) is a heterogeneous disease with respect to presentation and clinical outcome. The prognostic value of recently identified somatic mutations has not been systematically evaluated in a phase 3 trial of treatment for AML. We performed a mutational analysis of 18 genes in 398 patients younger than 60 years of age who had AML and who were randomly assigned to receive induction therapy with high-dose or standard-dose daunorubicin. We validated our prognostic findings in an independent set of 104 patients. We identified at least one somatic alteration in 97.3% of the patients. We found that internal tandem duplication in FLT3 (FLT3-ITD), partial tandem duplication in MLL (MLL-PTD), and mutations in ASXL1 and PHF6 were associated with reduced overall survival (P=0.001 for FLT3-ITD, P=0.009 for MLL-PTD, P=0.05 for ASXL1, and P=0.006 for PHF6); CEBPA and IDH2 mutations were associated with improved overall survival (P=0.05 for CEBPA and P=0.01 for IDH2). The favorable effect of NPM1 mutations was restricted to patients with co-occurring NPM1 and IDH1 or IDH2 mutations. We identified genetic predictors of outcome that improved risk stratification among patients with AML, independently of age, white-cell count, induction dose, and post-remission therapy, and validated the significance of these predictors in an independent cohort. High-dose daunorubicin, as compared with standard-dose daunorubicin, improved the rate of survival among patients with DNMT3A or NPM1 mutations or MLL translocations (P=0.001) but not among patients with wild-type DNMT3A, NPM1, and MLL (P=0.67). We found that DNMT3A and NPM1 mutations and MLL translocations predicted an improved outcome with high-dose induction chemotherapy in patients with AML. These findings suggest that mutational profiling could potentially be used for risk stratification and to inform prognostic and therapeutic decisions regarding patients with AML. (Funded by the National Cancer Institute and others.).
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            The distinct metabolic profile of hematopoietic stem cells reflects their location in a hypoxic niche.

            Bone marrow transplantation is the primary therapy for numerous hematopoietic disorders. The efficiency of bone marrow transplantation depends on the function of long-term hematopoietic stem cells (LT-HSCs), which is markedly influenced by their hypoxic niche. Survival in this low-oxygen microenvironment requires significant metabolic adaptation. Here, we show that LT-HSCs utilize glycolysis instead of mitochondrial oxidative phosphorylation to meet their energy demands. We used flow cytometry to identify a unique low mitochondrial activity/glycolysis-dependent subpopulation that houses the majority of hematopoietic progenitors and LT-HSCs. Finally, we demonstrate that Meis1 and Hif-1alpha are markedly enriched in LT-HSCs and that Meis1 regulates HSC metabolism through transcriptional activation of Hif-1alpha. These findings reveal an important transcriptional network that regulates HSC metabolism. Copyright 2010 Elsevier Inc. All rights reserved.
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              Deep imaging of bone marrow shows non-dividing stem cells are mainly perisinusoidal

              Hematopoietic stem cells (HSCs) reside in a perivascular niche but the location remains controversial 1 . HSCs are rare and few can be found in thin tissue sections 2,3 or upon live imaging 4 , making it difficult to comprehensively localize dividing and non-dividing HSCs. We discovered that α-catulinGFP/+ was expressed by only 0.02% of bone marrow hematopoietic cells, including virtually all HSCs. One in 3.5 α-catulin-GFP+c-kit+ cells gave long-term multilineage reconstitution of irradiated mice, indicating that α-catulin-GFP+c-kit+ cells contain HSCs with a purity comparable to the best markers available. We were able to optically clear the bone marrow to perform deep confocal imaging, making it possible to image thousands of α-catulin-GFP+c-kit+ cells and to digitally reconstruct large segments of bone marrow. The distribution of α-catulin-GFP+c-kit+ cells indicated that HSCs were more common in central marrow than near bone surfaces and in the diaphysis relative to the metaphysis. Nearly all HSCs contacted Leptin Receptor+ and Cxcl12high niche cells. Approximately 85% of HSCs were within 10μm of a sinusoidal blood vessel. Most HSCs were distant from arterioles, transition zone vessels, and bone surfaces. This was true of Ki-67+ dividing HSCs and Ki-67− non-dividing HSCs. Dividing and non-dividing HSCs thus reside mainly in perisinusoidal niches with Leptin Receptor+Cxcl12high cells throughout the bone marrow.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                Nature
                0028-0836
                1476-4687
                15 August 2017
                21 August 2017
                28 September 2017
                20 April 2018
                : 549
                : 7673
                : 476-481
                Affiliations
                [1 ]Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
                [2 ]Children’s Research Institute and the Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
                [3 ]Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
                [4 ]Department of Medicine, University of Utah, Salt Lake City, Utah, USA
                Author notes
                [5 ]Correspondence and requests for materials should be addressed to S.J.M. ( Sean.Morrison@ 123456UTSouthwestern.edu )
                Article
                NIHMS899845
                10.1038/nature23876
                5910063
                28825709
                6a2f4344-f4a9-47c0-a49f-d2174b156816

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