Nadim Mahmud

University of Illinois at Chicago, Chicago, Illinois, United States

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Publications (76)340.48 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The mechanism responsible for developmental stage-specific regulation of γ-globin gene expression involves DNA methylation. Previous results have shown that the γ-globin promoter is nearly fully demethylated during fetal liver erythroid differentiation and partially demethylated during adult bone marrow erythroid differentiation. The hypothesis that 5-hydroxymethylcytosine (5hmC), a known intermediate in DNA demethylation pathways, is involved in demethylation of the γ-globin gene promoter during erythroid differentiation was investigated by analyzing levels of 5-methylcytosine (5mC) and 5hmC at a CCGG site within the 5' γ-globin gene promoter region in FACS-purified cells from baboon bone marrow and fetal liver enriched for different stages of erythroid differentiation. Our results show that 5mC and 5hmC levels at the γ-globin promoter are dynamically modulated during erythroid differentiation with peak levels of 5hmC preceding and/or coinciding with demethylation. The Tet2 and Tet3 dioxygenases that catalyze formation of 5hmC are expressed during early stages of erythroid differentiation and Tet3 expression increases as differentiation proceeds. In baboon CD34+ bone marrow-derived erythroid progenitor cell cultures, γ-globin γ-globin expression was positively correlated with 5hmC and negatively correlated with 5mC at the γ-globin promoter. Supplementation of culture media with Vitamin C, a cofactor of the Tet dioxygenases, reduced γ-globin promoter DNA methylation and increased γ-globin expression when added alone and in an additive manner in combination with either DNA methyltransferase or LSD1 inhibitors. These results strongly support the hypothesis that the Tet-mediated 5hmC pathway is involved in developmental stage-specific regulation of γ-globin expression by mediating demethylation of the γ-globin promoter.
    Epigenetics: official journal of the DNA Methylation Society 05/2015; DOI:10.1080/15592294.2015.1039220 · 5.11 Impact Factor
  • Nadim Mahmud, Donald Lavelle
    Blood 02/2015; 125(6):895-6. DOI:10.1182/blood-2014-11-609024 · 9.78 Impact Factor
  • Biology of Blood and Marrow Transplantation 02/2015; 21(2):S44-S45. DOI:10.1016/j.bbmt.2014.11.038 · 3.35 Impact Factor
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    ABSTRACT: Here we examined the addition of intensity-modulated total marrow irradiation (TMI), delivered using a linear accelerator (linac), to a myeloablative chemotherapy conditioning regimen prior to allogeneic hematopoietic stem cell transplantation (HSCT). In this phase I study we enrolled 14 patients with high-risk hematologic malignancies, who received escalating doses of TMI at 3Gy (n=3), 6Gy (n=3), 9Gy (n=6) and 12Gy (n=2) in combination with intravenous (i.v.) fludarabine 160mg/m2 and targeted busulfan (AUC 4800 μM*min). Peripheral blood mobilized stem cells were obtained from HLA matched related (n=9) or unrelated (n=4), or 1 antigen mismatched unrelated (n=1) donors. All patients rapidly engrafted and recovered their immune cells. Overall Bearman extrahematologic toxicity limited to grades 1 or 2 with oral mucositis grade 1 in 64% and grade 2 in 36% of the patients. With a median follow up of 1126 days (range 362-1469) for alive patients, the overall survival is 50% and relapse free survival 43%. Of 7 deaths, 3 were due to relapse and 4 to transplant-related complications. We conclude that 9Gy TMI can be combined with myeloablative chemotherapy in the design of new preparative regimens for HSCT. This study was registered at clinicaltrials.gov as NCT00988013.
    Biology of Blood and Marrow Transplantation 12/2014; 20(12). DOI:10.1016/j.bbmt.2014.09.005 · 3.35 Impact Factor
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    ABSTRACT: Epigenetic modifications likely control the fate of hematopoietic stem cells (HSCs). The chromatin-modifying agents (CMAs), 5-aza-2'-deoxycytidine (5azaD) and trichostatin A (TSA), have previously been shown to expand HSCs from cord blood and marrow. Here we assessed whether CMA can also expand HSCs present in growth factor-mobilized human peripheral blood (MPB).
    Transfusion 11/2014; DOI:10.1111/trf.12904 · 3.57 Impact Factor
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    ABSTRACT: Glutathione peroxidase activity was previously determined to be elevated in lymphocytes obtained from patients treated with the Bcr-Abl kinase inhibitor imatinib mesylate. In order to expand upon this observation, the established chronic myelogenous leukemia cell lines KU812 and MEG-01 were treated with imatinib and the effect on several anti-oxidant proteins was determined. The levels of GPx-1 were significantly increased following treatment with imatinib. This increase was not due to altered steady-state mRNA levels, and appeared to be dependent on the expression of Bcr-Abl, as no increases were observed following imatinib treatment of cells that did not express the fusion protein. The nutrient-sensing signaling protein, mammalian target of rapamycin (mTOR), can be activated by Bcr-Abl and its activity regulates the translation of many different proteins. Treatment of those same cells used in the imatinib studies with rapamycin, an inhibitor of mTOR, resulted in elevated GPx-1 and GPx-4 protein levels independent of Bcr-Abl expression. These proteins all belong to the selenoprotein family of peptides that contain the UGA-encoded amino acid selenocysteine. Collectively, these data provide evidence of a novel means of regulating anti-oxidants of the selenoprotein family via the mTOR pathway.
    PLoS ONE 04/2014; 9(4):e93472. DOI:10.1371/journal.pone.0093472 · 3.53 Impact Factor
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    ABSTRACT: Adult stem cell-based therapy is a promising novel approach for treatment of acute lung injury. Here we investigated the therapeutic potential of freshly isolated human umbilical cord blood CD34(+) progenitor cells (fCB-CD34(+) cells) in a mouse model of acute lung injury. At 3 h post-lipopolysaccharide (LPS) challenge, fCB-CD34(+) cells were transplanted i.v. to mice while CD34(-) cells or PBS were administered as controls in separate cohorts of mice. We observed that fCB-CD34(+) cell treatment inhibited lung vascular injury evident by decreased lung vascular permeability. In contrast, CD34(-) cells had no effects on lung vascular injury. Lung inflammation determined by myeloperoxidase activity, neutrophil sequestration and expression of pro-inflammatory mediators was attenuated in fCB-CD34(+) cell-treated mice at 26 h post-LPS challenge compared to PBS or CD34(-) cell-treated controls. Importantly, lung inflammation in fCB-CD34(+) cell-treated mice was returned to normal levels as seen in basal mice at 52 h post-LPS challenge whereas PBS or CD34(-) cell-treated control mice exhibited persistent lung inflammation. Accordingly, fCB-CD34(+) cell-treated mice exhibited a marked increase of survival rate. Employing in vivo 5-bromo-2'-deoxyuridine incorporation assay, we found a drastic induction of lung endothelial proliferation in fCB-CD34(+) cell-treated mice at 52 h post-LPS compared to PBS or CD34(-) cell-treated controls, which contributed to restoration of vascular integrity and thereby inhibition of lung inflammation. Taken together, these data have demonstrated the protective effects of fCB-CD34(+) cell on acute lung injury induced by LPS challenge, suggesting fCB-CD34(+) cells are an important source of stem cells for the treatment of acute lung injury.
    PLoS ONE 02/2014; 9(2):e88814. DOI:10.1371/journal.pone.0088814 · 3.53 Impact Factor
  • Biology of Blood and Marrow Transplantation 02/2014; 20(2):S244-S245. DOI:10.1016/j.bbmt.2013.12.411 · 3.35 Impact Factor
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    ABSTRACT: Epigenetic therapies, including DNA methyltransferase and histone deacetylase (HDAC) inhibitors, are increasingly being considered to treat haematological malignancies, while their effects on normal hematopoietic stem cells (HSC) remain largely unexplored. We compared the effects of several HDAC inhibitors, including valproic acid (VPA) and trichostatin A (TSA), alone or in combination with 5-aza-2'-deoxycytidine (5azaD) on the expansion of HSCs. VPA induced the highest expansion of CD34+CD90+ cells and progenitor cells compared with other HDAC inhibitors or the sequential addition of 5azaD/TSA in culture. Xeno-transplantation studies demonstrated that VPA prevents HSC loss, while 5azaD/TSA treatment leads to a net expansion of HSCs that retain serial transplantation ability. 5azaD/TSA-mediated HSC expansion was associated with increased histone acetylation and transient DNA demethylation, which corresponded with higher gene transcript levels. However, some genes with increased transcript levels lacked changes in methylation. Importantly, a global microarray analysis revealed a set of differentially expressed genes in 5azaD/TSA- and VPA-expanded CD34+ cells that might be involved in the expansion and maintenance of transplantable HSCs, respectively. In summary, our data indicate that treatment of HSCs with different chromatin-modifying agents (CMAs) results in either the expansion or maintenance of HSCs, an observation of potential therapeutic importance.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 12/2013; 20(4). DOI:10.1016/j.bbmt.2013.12.562 · 3.35 Impact Factor
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    ABSTRACT: Many tumors are stiffer than their surrounding tissue. This increase in stiffness has been attributed, in part, to a Rho-dependent elevation of myosin II light chain phosphorylation. To characterize this mechanism further, we studied myosin light chain kinase (MLCK), the main enzyme that phosphorylates myosin II light chains. We anticipated that increases in MLCK expression and activity would contribute to the increased stiffness of cancer cells. However, we find that MLCK mRNA and protein levels are substantially less in cancer cells and tissues than in normal cells. Consistent with this observation, cancer cells contract 3D collagen matrices much more slowly than normal cells. Interestingly, inhibiting MLCK or Rho kinase did not affect the 3D gel contractions while blebbistatin partially and cytochalasin D maximally inhibited contractions. Live cell imaging of cells in collagen gels showed that cytochalasin D inhibited filopodia-like projections that formed between cells while a MLCK inhibitor had no effect on these projections. These data suggest that myosin II phosphorylation is dispensable in regulating the mechanical properties of tumors.
    PLoS ONE 11/2013; 8(11):e79776. DOI:10.1371/journal.pone.0079776 · 3.53 Impact Factor
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    ABSTRACT: PURPOSE. To characterize fluorescent bone marrow cells (YFP+ BMCs) in the thy1-YFP mouse and determine if they promote trigeminal ganglion (TG) cell neurite growth. METHODS. Excimer laser annular keratectomy was performed in thy1-YFP mice, and corneas were imaged. BMCs were harvested from femur and tibia and the expression of surface markers on YFP+ BMCs was analyzed by flow cytometry. The immunosuppressive action of BMCs (YFP+ and YFP-) was evaluated in an allogenic mixed lymphocyte reaction (MLR). Neurotrophic action of BMCs (YFP+ and YFP-) was determined in compartmental and transwell cultures of dissociated TG cells. RESULTS. Following annular keratectomy, YFP+ BMCs infiltrated the cornea. YFP+ BMCs shared surface markers (CD11b+Gr1+Ly6C+Ly6G-F4/80low) with monocytic myeloid-derived suppressor cells (MDSC), had similar morphology, and suppressed T cell proliferation in allogenic MLR in a dose-dependent manner. YFP+ BMCs, but not YFP- BMCs, significantly increased growth of TG neurites in vitro. When cultured in a transwell with TG neurites, YFP+ BMCs expressed neurotrophins and secreted nerve growth factor (NGF) in conditioned medium. YFP+ BMCs that infiltrated the cornea maintained their phenotype and actions (neuronal and immune). CONCLUSIONS. YFP+ BMCs in thy1-YFP mice have immunophenotypic features of MDSCs. They secrete NGF and promote neuroregeneration. Their immunosuppressive and neurotrophic actions are preserved after corneal infiltration. These findings increase our understanding of the beneficial roles played by leukocyte trafficking in the cornea and may lead to therapeutic strategies that use NGF-secreting myeloid cells to repair diseased or injured neurons.
    Investigative ophthalmology & visual science 08/2013; 54(9). DOI:10.1167/iovs.13-12237 · 3.66 Impact Factor
  • Biology of Blood and Marrow Transplantation 02/2013; 19(2):S335-S336. DOI:10.1016/j.bbmt.2012.11.512 · 3.35 Impact Factor
  • Bone marrow transplantation 11/2012; DOI:10.1038/bmt.2012.212 · 3.47 Impact Factor
  • Bone marrow transplantation 08/2012; 48(2). DOI:10.1038/bmt.2012.148 · 3.47 Impact Factor
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    ABSTRACT: This study was performed to investigate the hypothesis that the erythroid micro-environment plays a role in regulation of globin gene expression during adult erythroid differentiation. Adult baboon bone marrow and human cord blood CD34+ progenitors were grown in methylcellulose, liquid media, and in co-culture with stromal cell lines derived from different developmental stages in identical media supporting erythroid differentiation to examine the effect of the micro-environment on globin gene expression. Adult progenitors express high levels of γ-globin in liquid and methylcellulose media but low, physiological levels in stromal cell co-cultures. In contrast, γ-globin expression remained high in cord blood progenitors in stromal cell line co-cultures. Differences in γ-globin gene expression between adult progenitors in stromal cell line co-cultures and liquid media required cell-cell contact and were associated with differences in rate of differentiation and γ-globin promoter DNA methylation. We conclude that γ-globin expression in adult-derived erythroid cells can be influenced by the micro-environment, suggesting new potential targets for HbF induction.
    PLoS ONE 05/2012; 7(5):e36846. DOI:10.1371/journal.pone.0036846 · 3.53 Impact Factor
  • Biology of Blood and Marrow Transplantation 02/2012; 18(2):S329-S330. DOI:10.1016/j.bbmt.2011.12.329 · 3.35 Impact Factor
  • Biology of Blood and Marrow Transplantation 02/2012; 18(2):S296-S297. DOI:10.1016/j.bbmt.2011.12.238 · 3.35 Impact Factor
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    ABSTRACT: Cotransplantation of human CD34(+) hematopoietic stem cells (HSC) and CD4(+)CD25(+)FoxP3(+) regulatory T cells (Tregs) could prevent anti-HSC alloreactivity and reduce the risk of rejection in HLA mismatched transplants. To pursue this hypothesis we cocultured CD34(+) cells and CD4(+)CD25(+) cells immunomagnetically isolated (Milteny) from human peripheral blood (unmanipulated or granulocyte-colony stimulating factor [G-CSF] mobilized) or cord blood. Enriched Tregs obtained from the same source (autologous) of CD34(+) cells showed greater inhibitory effect on T cell alloreactivity than third-party (allogeneic) Tregs. The immunosuppressive activity of Tregs was maintained after stimulation with allogeneic CD34(+) cells and Tregs did not modify the clonogenic activity of CD34(+) cells in vitro. Cotransplantation of Tregs with CD34(+) cells at 1:1 or 2:1 ratios in nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice resulted in normal hematopoietic stem cell engraftment. Incubation with physiologic doses of rabbit antithymocyte globulin (rATG, thymoglobulin) did not affect the number of Tregs in 6-day culture. Upon exposure to thymoglobulin Tregs maintained their suppressive activity, increased expression of CCR7, and released multiple cytokines, primarily interleukin (IL)10. Our findings suggest that human autologous or allogeneic Tregs could be cotransplanted with CD34(+) cells after preparative regimens including thymoglobulin.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 01/2011; 17(1):61-8. DOI:10.1016/j.bbmt.2010.08.004 · 3.35 Impact Factor
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    ABSTRACT: Increased cell dose has a positive impact on the therapeutic outcome of bone marrow (BM) hematopoietic stem cell (HSC) transplant. However, methods to successfully expand BM HSCs have yet to be achieved. It has been shown previously that ex vivo expansion of BM cells using porcine microvascular endothelial cells can rescue a baboon from a lethal dose of radiation. However, in a prior study, baboons that received CD34+ cell doses less than 4 x 10(6) cells/kg body weight failed to achieve hematopoietic reconstitution. In our present study we used human brain endothelial cells (HUBECs) and cytokines to expand BM cells, and examined their ability to provide hematopoietic reconstitution in three lethally irradiated baboons following autologous transplant as a surrogate preclinical model. After ex vivo culture, the grafts represented a 1.8- to 2.1-fold expansion of CD34+ cells, a 3.7- to 13.2-fold increase of colony-forming cells, and a 1.9- to 3.2-fold increase of cobblestone area-forming cells, in comparison to the input cell numbers. Despite transplanting CD34+ cell grafts displaying a comparable degree of expansion, there was an obvious variability in the kinetics of hematopoietic reconstitution. The variation in hematopoietic reconstitution cannot be fully explained by the properties tested in expanded CD34+ cells, and warrant caution against taking into account such attributes as cell dose, expression of adhesion molecules, and migration as a measure of successful expansion of HSCs.
    Leukemia & lymphoma 06/2010; 51(6):1121-7. DOI:10.3109/10428191003786774 · 2.61 Impact Factor
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    ABSTRACT: Of all living experimental models, murine studies of hematopoiesis represent the greatest number. Such models can be undeniably elegant reflecting the extensive technological tools available. While mice can be used to study specific genetic pedigrees, specific physiologic, and gene pathways using knockouts, and a variety of immune responses using immunologically deficient mice, murine models are limited in their applicability for clinical use. Rodents differ from humans in many aspects including their short lifespan, difference in the rate of doubling of hematopoietic stem/progenitor cells, and the responses of blood cells to the hematological stresses of radiation and cytotoxic agents [1-5].
    02/2010: pages 767-787;

Publication Stats

1k Citations
340.48 Total Impact Points

Institutions

  • 2000–2015
    • University of Illinois at Chicago
      • • Section of Hematology and Oncology
      • • Department of Medicine (Chicago)
      Chicago, Illinois, United States
  • 2005
    • Baylor College of Medicine
      Houston, Texas, United States
  • 1994
    • Mie University
      • Third Department of Internal Medicine
      Tu, Mie, Japan