Ronan Desmond

Tallaght Hospital, Tallaght, Leinster, Ireland

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Publications (11)139.05 Total impact

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    ABSTRACT: Hematopoietic stem and progenitor cells (HSPC) reside in a specialized niche that regulates their proliferative capacity and their fate. There is increasing evidence for similar roles of marrow niches on controlling the behavior of leukemic cells, however whether normal HSC and leukemic cells reside in or functionally compete for the same marrow niche is unclear. We used the MLL-AF9 murine acute myeloid leukemia in a competitive repopulation model to investigate whether normal HSPC and leukemic cells functionally compete for the same marrow niches. Irradiated recipient mice were transplanted with fixed numbers of MLL-AF9 cells mixed with increasing doses of normal syngeneic whole bone marrow (WBM) or with purified HSPC (LSK). Survival was significantly increased and leukemic progression was delayed proportional to increasing doses of normal WBM or normal LSK cells in multiple independent experiments, with all doses of WBM or LSK cells studied above the threshold for rapid and complete hematopoietic reconstitution in the absence of leukemia. Confocal microscopy demonstrated nests of either leukemic cells or normal hematopoietic cells but not both in the marrow adjacent to endosteum. Early following transplantation, leukemic cells from animals receiving lower LSK doses were cycling more actively than in those receiving higher doses. These results suggest that normal HSPC and AML cells compete for the same functional niche. Manipulation of the niche could impact on response to anti-leukemic therapies, and the numbers of normal HSPC could impact on leukemia outcome, informing approaches to cell dose in the context of stem cell transplantation. This article is protected by copyright. All rights reserved.
    Stem Cells 09/2015; DOI:10.1002/stem.2208 · 6.52 Impact Factor
  • Leukemia Research 04/2015; 39:S26-S27. DOI:10.1016/S0145-2126(15)30057-6 · 2.35 Impact Factor
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    ABSTRACT: Chromothripsis is a catastrophic cellular event recently described in cancer in which chromosomes undergo massive deletion and rearrangement. Here, we report a case in which chromothripsis spontaneously cured a patient with WHIM syndrome, an autosomal dominant combined immunodeficiency disease caused by gain-of-function mutation of the chemokine receptor CXCR4. In this patient, deletion of the disease allele, CXCR4(R334X), as well as 163 other genes from one copy of chromosome 2 occurred in a hematopoietic stem cell (HSC) that repopulated the myeloid but not the lymphoid lineage. In competitive mouse bone marrow (BM) transplantation experiments, Cxcr4 haploinsufficiency was sufficient to confer a strong long-term engraftment advantage of donor BM over BM from either wild-type or WHIM syndrome model mice, suggesting a potential mechanism for the patient's cure. Our findings suggest that partial inactivation of CXCR4 may have general utility as a strategy to promote HSC engraftment in transplantation. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell 02/2015; 160(4). DOI:10.1016/j.cell.2015.01.014 · 32.24 Impact Factor
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    ABSTRACT: The treatment of aplastic anemia is currently with immunosuppressive therapy (IST) with anti-thymocyte globulin (ATG) and cyclosporine, to which two thirds of patients respond. However, a significant proportion of these responders relapse and many have persistent cytopenias. The management of these patients is challenging. Modifications to this standard approach using alternative immunosuppressive agents or adding hematopoietic cytokines such as granulocyte colony-stimulating factor (G-CSF) and erythropoietin (EPO) have not improved outcome. A recent trial has shown that eltrombopag, a thrombopoeitin mimetic, is efficacious in the treatment of patients with severe aplastic anemia (SAA) refractory to IST. There is evidence that this drug works by directly stimulating marrow stem and progenitor cells thereby promoting hematopoietic recovery in patients with bone marrow failure. Several trials are ongoing in our institution using this very promising drug in combination therapy in the upfront treatment of SAA, in IST-refractory SAA and in moderate disease. Published by Elsevier Inc.
    Seminars in Hematology 01/2015; 52(1):31-37. DOI:10.1053/j.seminhematol.2014.10.002 · 3.27 Impact Factor
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    ABSTRACT: About a quarter of patients with severe aplastic anemia (SAA) remain pancytopenic despite immunosuppressive therapy. We have previously demonstrated that eltrombopag has efficacy in this setting with 44% (11/25) of patients having clinically significant hematologic responses. We now report safety and efficacy data on a further 18 patients and long term follow up on the entire cohort of 43 patients. The overall response rate was 17/43 (40%) at 3-4 months, including tri and bi-lineage responses. The majority of patients who remained on eltrombopag in an extension study (14/17) continued to show improvement, and 7 eventually had significant increases in neutrophil, red cell and platelet lineages. Five patients with robust near-normalization of blood counts had drug discontinued at a median of 28.5 months after entry (range 9 to 37), and all maintained stable counts a median of 13 months (range 1-15) off eltrombopag. 8 patients, including 6 non-responders and 2 responders, developed new cytogenetic abnormalities on eltrombopag, including 5 with chromosome 7 loss or partial deletion. None evolved to acute myeloid leukemia to date. Eltrombopag is efficacious in a subset of patients with aplastic anemia refractory to IST, with frequent multilineage responses, and maintenance of normalized hematopoiesis off treatment. This study is registered at, identifier: NCT00922883.
    Blood 12/2013; 123(12). DOI:10.1182/blood-2013-10-534743 · 10.45 Impact Factor
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    ABSTRACT: Aplastic anemia is a bone marrow failure syndrome that causes pancytopenia and can lead to life-threatening complications. Bone marrow transplantation remains the standard of care for younger patients and those with a good performance status but many patients may not have a suitable donor. Immunosuppressive therapy is able to resolve cytopenias in a majority of patients with aplastic anemia but relapses are not uncommon and some patients remain refractory to this approach. Patients may require frequent blood and platelet transfusion support which is expensive and inconvenient. Life-threatening bleeding complications still occur despite prophylactic platelet transfusion. Thrombopoietin (TPO) mimetics, such as romiplostim and eltrombopag, were developed to treat patients with refractory immune thrombocytopenia but are now being investigated for the treatment of bone marrow failure syndromes. TPO is the main regulator for platelet production and its receptor (c-Mpl) is present on megakaryocytes and hematopoietic stem cells. Trilineage hematopoietic responses were observed in a recent clinical trial using eltrombopag in patients with severe aplastic anemia refractory to immunosuppression suggesting that these agents can provide a new therapeutic option for enhancing blood production. In this review, we discuss these recent results and ongoing investigation of TPO mimetics for aplastic anemia and other bone marrow failure states like myelodysplastic syndromes. Clonal evolution or progression to acute myeloid leukemia remains a concern when using these drugs in bone marrow failure and patients should only be treated in the setting of a clinical trial.
    International journal of hematology 05/2013; 98(1). DOI:10.1007/s12185-013-1352-6 · 1.92 Impact Factor
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    ABSTRACT: Severe aplastic anemia, which is characterized by immune-mediated bone marrow hypoplasia and pancytopenia, can be treated effectively with immunosuppressive therapy or allogeneic transplantation. One third of patients have disease that is refractory to immunosuppression, with persistent, severe cytopenia and a profound deficit in hematopoietic stem cells and progenitor cells. Thrombopoietin may increase the number of hematopoietic stem cells and progenitor cells. We conducted a phase 2 study involving patients with aplastic anemia that was refractory to immunosuppression to determine whether the oral thrombopoietin mimetic eltrombopag (Promacta) can improve blood counts. Twenty-five patients received eltrombopag at a dose of 50 mg, which could be increased, as needed, to a maximum dose of 150 mg daily, for a total of 12 weeks. Primary end points were clinically significant changes in blood counts or transfusion independence. Patients with a response continued to receive eltrombopag. Eleven of 25 patients (44%) had a hematologic response in at least one lineage at 12 weeks, with minimal toxic effects. Nine patients no longer needed platelet transfusions (median increase in platelet count, 44,000 per cubic millimeter). Six patients had improved hemoglobin levels (median increase, 4.4 g per deciliter); 3 of them were previously dependent on red-cell transfusions and no longer needed transfusions. Nine patients had increased neutrophil counts (median increase, 1350 per cubic millimeter). Serial bone marrow biopsies showed normalization of trilineage hematopoiesis in patients who had a response, without increased fibrosis. Monitoring of immune function revealed no consistent changes. Treatment with eltrombopag was associated with multilineage clinical responses in some patients with refractory severe aplastic anemia. (Funded by the National Heart, Lung, and Blood Institute; number, NCT00922883.).
    New England Journal of Medicine 07/2012; 367(1):11-9. DOI:10.1056/NEJMoa1200931 · 55.87 Impact Factor
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    ABSTRACT: Manipulation of hematopoietic stem/progenitor cells (HSPCs) ex vivo is of clinical importance for stem cell expansion and gene therapy applications. However, most cultured HSPCs are actively cycling, and show a homing and engraftment defect compared with the predominantly quiescent noncultured HSPCs. We previously showed that HSPCs make contact with osteoblasts in vitro via a polarized membrane domain enriched in adhesion molecules such as tetraspanins. Here we show that increased cell cycling during ex vivo culture of HSPCs resulted in disruption of this membrane domain, as evidenced by disruption of polarity of the tetraspanin CD82. Chemical disruption or antibody-mediated blocking of CD82 on noncultured HSPCs resulted in decreased stromal cell adhesion, homing, and engraftment in nonobese diabetic/severe combined immunodeficiency IL-2γ(null) (NSG) mice compared with HSPCs with an intact domain. Most leukemic blasts were actively cycling and correspondingly displayed a loss of domain polarity and decreased homing in NSG mice compared with normal HSPCs. We conclude that quiescent cells, unlike actively cycling cells, display a polarized membrane domain enriched in tetraspanins that mediates homing and engraftment, providing a mechanistic explanation for the homing/engraftment defect of cycling cells and a potential new therapeutic target to enhance engraftment.
    Blood 02/2012; 119(8):1848-55. DOI:10.1182/blood-2011-08-371583 · 10.45 Impact Factor
  • Blood 05/2011; 117(21):5774-6. DOI:10.1182/blood-2011-01-332031 · 10.45 Impact Factor
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    American Journal of Hematology 08/2009; 85(8):607. DOI:10.1002/ajh.21589 · 3.80 Impact Factor
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    P T Murphy · S Mitra · M Gleeson · R Desmond · D W Swinkels
    British Journal of Haematology 12/2008; 144(3):451-2. DOI:10.1111/j.1365-2141.2008.07455.x · 4.71 Impact Factor
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    R Desmond · J McDerra · K Kelly · O Smith
    British Journal of Haematology 11/2008; 144(5):627. DOI:10.1111/j.1365-2141.2008.07396.x · 4.71 Impact Factor

Publication Stats

116 Citations
139.05 Total Impact Points


  • 2015
    • Tallaght Hospital
      Tallaght, Leinster, Ireland
  • 2012–2015
    • National Heart, Lung, and Blood Institute
      • Hematology Branch
      베서스다, Maryland, United States
    • National Institutes of Health
      • Department of Laboratory Medicine
      Maryland, United States
  • 2008–2009
    • Beaumont Hospital
      Dublin, Leinster, Ireland
    • Our Ladys Childrens Hospital, Crumlin
      Dublin, Leinster, Ireland