Lori Mainwaring

Howard Hughes Medical Institute, Ashburn, Virginia, United States

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Publications (6)38.9 Total impact

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    ABSTRACT: We examined expression profiles of hematopoietic tissue-specific microRNAs (miRNAs; miR-142, miR-155, miR-181 and miR-223) in 17 commercially available malignant hematopoietic cell lines and compared to those in highly purified normal human B, T, monocytic and granulocytic lineages. Although malignant cell lines examined showed miRNA expression patterns similar to normal human hematopoietic lineages, the levels of miRNA expression among cell lines and normal cell lineages were considerably different, indicating the significance of miRNAs in human hematopoietic diseases. Further our results showed differences in miRNA expression between mouse and human hematopoietic cells, suggesting important regulatory roles of miRNAs in human hematopoiesis and oncogenesis.
    Leukemia Research 06/2006; 30(5):643-7. · 2.76 Impact Factor
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    ABSTRACT: MicroRNAs (miRNAs) are an important class of endogenously derived, small approximately 22 nucleotide noncoding regulatory RNAs that have recently become implicated in development, cell regulation and cancers of various tissues. Here we report a nonisotopic Northern analysis method for miRNA detection using 3'-digoxigenin (DIG)-labeled RNA oligo probes. Northern blot analysis was performed using miRNA or total RNA fractions extracted from human leukemic cell lines, and blots were hybridized with either 32P- or DIG-labeled RNA probe for miR-181, miR-155 or miR-16. A labeled probe for U6 small nuclear RNA served as an internal control. The use of DIG-labeled RNA probes was equally sensitive compared to 32P-labeled probes in detecting miRNA quantities as low as 50 ng. The ability to use nonisotopic methods and yet obtain sensitive and reliable results offers an advantage to investigators who prefer to avoid isotopes.
    Molecular and Cellular Probes 03/2006; 20(1):1-4. · 1.87 Impact Factor
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    ABSTRACT: Clinical observations and experimental evidence link bone marrow failure in myelodysplastic syndrome (MDS) with a T cell-dominated autoimmune process. Immunosuppressive therapy is effective in improving cytopenias in selected patients. Trisomy 8 is a frequent cytogenetic abnormality in bone marrow cells in patients with MDS, and its presence has been associated anecdotally with good response to immunotherapy. We studied 34 patients with trisomy 8 in bone marrow cells, some of whom were undergoing treatment with antithymocyte globulin (ATG). All had significant CD8+ T-cell expansions of one or more T-cell receptor (TCR) Vbeta subfamilies, as measured by flow cytometry; expanded subfamilies showed CDR3 skewing by spectratyping. Sorted T cells of the expanded Vbeta subfamilies, but not of the remaining subfamilies, inhibited trisomy 8 cell growth in short-term hematopoietic culture. The negative effects of Vbeta-expanded T cells were inhibited by major histocompatibility complex (MHC) class 1 monoclonal antibody (mAb) and Fas antagonist and required direct cell-to-cell contact. Sixty-seven percent of patients who had de novo MDS with trisomy 8 as the sole karyotypic abnormality responded to ATG with durable reversal of cytopenias and restoration of transfusion independence, with stable increase in the proportion of trisomy 8 bone marrow cells and normalization of the T-cell repertoire. An increased number of T cells with apparent specificity for trisomy 8 cells is consistent with an autoimmune pathophysiology in trisomy 8 MDS.
    Blood 09/2005; 106(3):841-51. · 9.78 Impact Factor
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    ABSTRACT: In paroxysmal nocturnal hemoglobinuria (PNH), an acquired mutation of the PIGA gene results in the absence of glycosylphosphatidylinositol (GPI)-anchored cell surface membrane proteins in affected hematopoietic cells. Absence of GPI-anchored proteins on erythrocytes is responsible for their increased sensitivity to complement-mediated lysis, resulting in hemolytic anemia. Cell-to-cell transfer of CD55 and CD59, 2 GPI-anchored proteins, by red cell microvesicles has been demonstrated in vitro, with retention of their function. Because red cell units stored for transfusion contain many erythrocyte microvesicles, transfused blood could potentially serve as a source of CD55 and CD59. We examined whether GPI-anchored proteins could be transferred in vivo to deficient cells following transfusions given to 6 patients with PNH. All patients were group A(1) blood type. Each was given transfusions of 3 U of compatible, washed group O blood. Patient group A(1) cells were distinguished from the transfused group O cells by flow cytometry and staining with a labeled lectin, Dolichos biflorus, which specifically binds to group A(1) erythrocytes. Increased surface CD59 was measured on recipient red cells and granulocytes 1, 3, and 7 days following transfusion in all 6 patients. Our data suggest a potential therapeutic role for GPI-anchored protein transfer for severe PNH.
    Blood 01/2005; 104(12):3782-8. · 9.78 Impact Factor
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    ABSTRACT: Clinical observations suggest that in chronic myelogenous leukemia (CML), the Philadelphia chromosome (Ph+) clone has a growth advantage over normal hematopoiesis. Patients with CML have high levels of neutrophil elastase, which has recently been shown to antagonize the action of granulocyte-colony-stimulating factor (G-CSF) and other growth factors. We therefore compared the effect of elastase on the growth of normal and CML progenitor cells. In 10-day suspension cultures of normal or CML CD34+ cells supplemented with G-CSF, stem cell factor (SCF), and granulocyte macrophage-colony-stimulating factor (GM-CSF), CML cells had diminished sensitivity to the growth inhibitory effect of elastase. When equal numbers of CML and normal CD34+ cells were cocultured for 10 days, there was no change in the relative proportions of normal and leukemic cells (measured by fluorescence in situ hybridization [FISH] or flow cytometry). However, when elastase was added, CML cells predominated at the end of the culture period (78% vs 22% with 1 microg/mL and 80% vs 20% with 5 microg/mL elastase). CML neutrophils substituted effectively for elastase in suppressing the proliferation of normal CD34+ cells, but this effect was abrogated by serine protease inhibitors. These results suggest that elastase overproduction by the leukemic clone can change the growth environment by digesting growth factors, thereby giving advantage to Ph+ hematopoiesis.
    Blood 12/2003; 102(10):3786-92. · 9.78 Impact Factor
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    ABSTRACT: Some patients with paroxysmal nocturnal haemoglobinuria (PNH) have bone marrow findings characteristic of myelodysplastic syndrome. We studied nine PNH patients to determine whether these karyotypic abnormalities were more likely to occur in glycosylphosphatidylinositol-anchored protein (GPI-AP)-negative cells. Abnormal chromosome patterns were evident only in the GPI-AP-positive populations of the PNH clone in 8 of 9 cases studied. Purified GPI-AP-negative CD34 cells gave rise only to cells of normal karyotype, whereas the progeny of the GPI-AP-positive CD34 cells showed the karyotypic abnormality. These findings suggest that environmental factors, but not genetic instability of the GPI-AP-deficient clone, foster development or survival of haematopoietic cells with chromosomal abnormalities.
    British Journal of Haematology 11/2003; 123(1):173-6. · 4.94 Impact Factor