Hematology Commons^™

Dnmt3a Haploinsufficiency Provokes Hematologic Malignancy Of B-Lymphoid, T-Lymphoid, And Myeloid Lineage In Mice, Garland Michael Upchurch

Theses & Dissertations

DNA methyltransferase 3A (DNMT3A) is a master epigenetic regulator of benign and malignant hematopoiesis. To dissect the biological consequences of homozygous and heterozygous Dnmt3a inactivation in malignant hematopoiesis, we generated Dnmt3a homozygous null (Dnmt3a^Δ/Δ) and Dnmt3a heterozygous (Dnmt3a^+/–) mice and compared the presentations of hematologic malignancies between cohorts. Bi-allelic inactivation of Dnmt3a results in the presentation of mature lymphoid neoplasms resembling chronic lymphocytic leukemia (CLL; B220⁺CD19⁺CD5⁺; 88% penetrance (37/42)) and CD8+ peripheral T-cell lymphoma (PTCL; TCRβ⁺CD3⁺CD8⁺CD4^—; 40% penetrance (17/42)). …

Dox Inducible Idh2 R140q Expression In Stem Cells Results In Cell Death, Opposite Of Cancerous Overgrowth, Reuben Hogan

Undergraduate Research Symposium Posters

Mutations in isocitrate dehydrogenase (IDH) 1 or 2 are found in about 23% of acute myeloid leukemia (AML) samples and about 90% of gliomas. Mutations result in neomorphic function of the IDH enzyme that yields the novel molecule 2-hydroxyglutarate (2HG) instead of alpha-ketoglutarate (aKG). 2HG is known to be associated with hypermethylation of DNA and histones, a phenotype seen in AML. Our lab intends to study the mechanism by which hypermethylation is achieved and how this mechanism relates to the onset of cancer. In this experiment, we utilized a line of H9 stem cells which we had developed. These cells …

Improved Survival After Acute Graft-Versus-Host Disease Diagnosis In The Modern Era, H Khoury, T Wang, Michael T. Hemmer, D Couriel, A Alousi, Mitchell Cairo, J Pidala

NYMC Faculty Publications

Acute graft-versus-host disease remains a major threat to a successful outcome after allogeneic hematopoietic cell transplantation. While improvements in treatment and supportive care have occurred, it is unknown whether these advances have resulted in improved outcome specifically among those diagnosed with acute graft-versus-host disease. We examined outcome following diagnosis of grade II-IV acute graft-versus-host disease according to time period, and explored effects according to original graft-versus-host disease prophylaxis regimen and maximum overall grade of acute graft-versus-host disease. Between 1999 and 2012, 2,905 patients with acute myeloid leukemia (56%), acute lymphoblastic …

Autoimmune Hemolytic Anemia Associated With Babesiosis, Roshni Narurkar, Aleksandra Mamorska-Dyga, John Nelson, Delong Liu

NYMC Faculty Publications

BACKGROUND: Babesiosis is endemic in selected areas in North America. Babesia infection is commonly associated with anemia, thrombocytopenia, hyponatremia and elevated liver enzymes. Autoimmune hemolytic anemia (AIHA) is known to be caused by parasitic and viral infections but has not been well characterized. CASE PRESENTATION: We describe two cases diagnosed with babesiosis triggering severe AIHA. One case had history of splenectomy, and the other was an elderly patient. Older, immunocompromised and asplenic patients may be particularly at risk for post-babesiosis AIHA (PB-AIHA). CONCLUSIONS: The pathogenesis for conventional AIHA and PB-AIHA appears to be different, since splenectomy is a treatment for …

Aapt Diagnostic Criteria For Chronic Sickle Cell Disease Pain., Carlton Dampier, Tonya M Palermo, Deepika S Darbari, Kathryn Hassell, Wally Smith, William Zempsky

Pediatrics Faculty Publications

Pain in sickle cell disease (SCD) is associated with increased morbidity, mortality, and high health care costs. Although episodic acute pain is the hallmark of this disorder, there is an increasing awareness that chronic pain is part of the pain experience of many older adolescents and adults. A common set of criteria for classifying chronic pain associated with SCD would enhance SCD pain research efforts in epidemiology, pain mechanisms, and clinical trials of pain management interventions, and ultimately improve clinical assessment and management. As part of the collaborative effort between the Analgesic, Anesthetic, and Addiction Clinical Trial Translations Innovations Opportunities …

Post-Transfusion Purpura: A Case Report Of An Underdiagnosed Phenomenon, Hind Rafei, Raza Yunus, Samah Nassereddine

Medicine Faculty Publications

Post-transfusion purpura is a rare transfusion-related complication that often goes undiagnosed. It is due to alloimmunization against platelet antigens which leads to acute profound thrombocytopenia following the transfusion of any platelet-containing product (red blood cells or platelets). It is commonly seen in multiparous women. Here, we report a case of post-transfusion purpura in a 56-year-old multiparous woman who developed acute thrombocytopenia seven days following a packed red blood cell transfusion. We will discuss the clinical presentation, diagnosis, workup and treatment of this rare disease. It is important to recognize this entity separately and to include it in the differential diagnosis …

A Trial Of Unrelated Donor Marrow Transplantation For Children With Severe Sickle Cell Disease., Shalini Shenoy, Mary Eapen, Julie A. Panepinto, Brent R. Logan, Juan Wu, Allistair Abraham, Joel Brochstein, Sonali Chaudhury, Kamar Godder, Ann E. Haight, Kimberly A. Kasow, Kathryn Leung, Martin Andreansky, Monica Bhatia, Jignesh Dalal, Hilary Haines, Jennifer Jaroscak, Hillard M. Lazarus, John E. Levine, Lakshmanan Krishnamurti, David Margolis, Gail C. Megason, Lolie C. Yu, Michael A. Pulsipher, Iris Gersten, Nancy Difronzo, Mary M. Horowitz, Mark C. Walters, Naynesh Kamani

Manuscripts, Articles, Book Chapters and Other Papers

Children with sickle cell disease experience organ damage, impaired quality of life, and premature mortality. Allogeneic bone marrow transplant from an HLA-matched sibling can halt disease progression but is limited by donor availability. A Blood and Marrow Transplant Clinical Trials Network (BMT CTN) phase 2 trial conducted from 2008 to 2014 enrolled 30 children aged 4 to 19 years; 29 were eligible for evaluation. The primary objective was 1-year event-free survival (EFS) after HLA allele-matched (at HLA-A, -B, -C, and -DRB1 loci) unrelated donor transplant. The conditioning regimen included alemtuzumab, fludarabine, and melphalan. Graft-versus-host disease (GVHD) prophylaxis included calcineurin inhibitor, …

Pharmacokinetics And Bioequivalence Of A Liquid Formulation Of Hydroxyurea In Children With Sickle Cell Anemia., Jeremie H. Estepp, Chiara Melloni, Courtney D. Thornburg, Paweł Wiczling, Zora Rogers, Jennifer A. Rothman, Nancy S. Green, Robert Liem, Amanda M. Brandow, Shelley E. Crary, Thomas H. Howard, Maurine H. Morris, Andrew Lewandowski, Uttam Garg, William J. Jusko, Kathleen A. Neville, Best Pharmaceuticals For Children Act-Pediatric Trials Network Administrative Core Committee

Manuscripts, Articles, Book Chapters and Other Papers

Hydroxyurea (HU) is a crucial therapy for children with sickle cell anemia, but its off-label use is a barrier to widespread acceptance. We found HU exposure is not significantly altered by liquid vs capsule formulation, and weight-based dosing schemes provide consistent exposure. HU is recommended for all children starting as young as 9 months of age with sickle cell anemia (SCA; HbSS and HbSβspan(0) thalassemia); however; a paucity of pediatric data exists regarding the pharmacokinetics (PK) or the exposure-response relationship of HU. This trial aimed to characterize the PK of HU in children and to evaluate and compare the bioavailability …

Hydroxycarbamide Versus Chronic Transfusion For Maintenance Of Transcranial Doppler Flow Velocities In Children With Sickle Cell Anaemia-Tcd With Transfusions Changing To Hydroxyurea (Twitch): A Multicentre, Open-Label, Phase 3, Non-Inferiority Trial., Russell E Ware, Barry R Davis, William H Schultz, R Clark Brown, Banu Aygun, Sharada Sarnaik, Lori Luchtman-Jones, +Several Additional Authors

Pediatrics Faculty Publications

BACKGROUND: For children with sickle cell anaemia and high transcranial doppler (TCD) flow velocities, regular blood transfusions can effectively prevent primary stroke, but must be continued indefinitely. The efficacy of hydroxycarbamide (hydroxyurea) in this setting is unknown; we performed the TWiTCH trial to compare hydroxyurea with standard transfusions.

METHODS: TWiTCH was a multicentre, phase 3, randomised, open-label, non-inferiority trial done at 26 paediatric hospitals and health centres in the USA and Canada. We enrolled children with sickle cell anaemia who were aged 4-16 years and had abnormal TCD flow velocities (≥ 200 cm/s) but no severe vasculopathy. After screening, eligible …

Examination Of Reticulocytosis Among Chronically Transfused Children With Sickle Cell Anemia., Megha Kaushal, Colleen Byrnes, Zarir Khademian, Natalie Duncan, Naomi L. Luban, Jeffery L Miller, Ross Fasano, Emily R. Meier

Pediatrics Faculty Publications

Sickle cell anemia (SCA) is an inherited hemolytic anemia with compensatory reticulocytosis. Recent studies have shown that increased levels of reticulocytosis during infancy are associated with increased hospitalizations for SCA sequelae as well as cerebrovascular pathologies. In this study, absolute reticulocyte counts (ARC) measured prior to transfusion were analysed among a cohort of 29 pediatric SCA patients receiving chronic transfusion therapy (CTT) for primary and secondary stroke prevention. A cross-sectional flow cytometric analysis of the reticulocyte phenotype was also performed. Mean duration of CTT was 3.1 ± 2.6 years. Fifteen subjects with magnetic resonance angiography (MRA) -vasculopathy had significantly higher …

Acute Myeloid Leukaemia In Children: Experience At A Tertiary Care Facility Of Pakistan, Zehra Fadoo, Naureen Mushtaq, Saima Alvi, Muhammad Ali

Department of Paediatrics and Child Health

Objective: To document the demographics and outcome of children with Acute Myeloid Leukemia (AML) treated at a tertiary care facility of Pakistan.

Methods: A retrospective study was conducted at Aga Khan University on children (less than 15 years) diagnosed to have AML between January 2000 to May 2007.Total 40 cases were diagnosed out of which 37 charts were available for review.

Results: The average age of presentation was 8.5±4.5 years and 75% were males. The most common presenting feature was fever in 83% followed by bleeding in 41% and pallor in 39%. Initial WBC of > 100,000 was seen in 19% …

Skeletal Abnormalities In Mice Lacking Extracellular Matrix Proteins, Thrombospondin-1, Thrombospondin-3, Thrombospondin-5, And Type Ix Collagen, Karen L Posey, Kurt Hankenson, Alka C Veerisetty, Paul Bornstein, Jack Lawler, Jacqueline T Hecht

Faculty, Staff and Student Publications

Thrombospondin-5 (TSP5) is a large extracellular matrix glycoprotein found in musculoskeletal tissues. TSP5 mutations cause two skeletal dysplasias, pseudoachondroplasia and multiple epiphyseal dysplasia; both show a characteristic growth plate phenotype with retention of TSP5, type IX collagen (Col9), and matrillin-3 in the rough endoplasmic reticulum. Whereas most studies focus on defining the disease process, few functional studies have been performed. TSP5 knockout mice have no obvious skeletal abnormalities, suggesting that TSP5 is not essential in the growth plate and/or that other TSPs may compensate. In contrast, Col9 knockout mice have diminished matrillin-3 levels in the extracellular matrix and early-onset osteoarthritis. …

P27kip1 And P130 Cooperate To Regulate Hematopoietic Cell Proliferation In Vivo, Inês Soeiro, Azim Mohamedali, Hanna M. Romanska, Nicholas C. Lea, Emma S. Child, Janet Glassford, Stephen J. Orr, Claudia Roberts, Kikkeri N. Naresh, El-Nasir Lalani, David J. Mann, Roger J. Watson, N. Shaun B. Thomas, Eric W. -F. Lam

Department of Pathology and Laboratory Medicine

To investigate the potential functional cooperation between p27^Kip1 and p130 in vivo, we generated mice deficient for both p27^Kip1 and p130. In p27^Kip1−/−;p130^−/− mice, the cellularity of the spleens but not the thymi is significantly increased compared with that of their p27^Kip1−/− counterparts, affecting the lymphoid, erythroid, and myeloid compartments. In vivo cell proliferation is significantly augmented in the B and T cells, monocytes, macrophages, and erythroid progenitors in the spleens of p27^Kip1−/−; p130^−/− animals. Immunoprecipitation and immunodepletion studies indicate that p130 can compensate for the absence …

Flow Cytometric And Demographic Analysis Of T Cell Acute Lymphoblastic Leukemia In Pakistani Population., M R. Khawaja, S S. Allana, N N. Akbaral, S N. Adil, M. Khurshid, Shahid Pervez

Department of Pathology and Laboratory Medicine

Background: This study was carried out to analyze the proportion of T cell acute lymphoblastic leukemia (TALL) among all acute lymphoblastic leukemia (ALL) in Pakistani population and its correlation with the demographic features. Accuracy of cell surface markers used in flow cytometric analysis of the leukemic cells was also determined.

Methods: Data of 209 consecutive cases of acute lymphoblastic leukemia (ALL) presenting between July 1995 and July 2003 was analyzed. Flow cytometry was performed on all ALL cases using the standard protocols. TALL markers included CD3, CD5 and CD7.

Results: Proportion of TALL among known ALL Pakistani patients was 17.22%. …

Spectrum Of Hodgkin's Disease In Children And Adults: Impact Of Combined Morphologic And Phenotypic Approach For Exclusion Of Look-Alikes, Tanya Siddiqui, Shahid Pervez

Department of Pathology and Laboratory Medicine

Objective:

To determine the prevalence of Hodgkin’s disease (HD) and its various subtypes in children and adults and assess the use of immunohistochemical (IHC) studies in confirming HD cases and excluding its close mimicries/look-alikes.

Material and Methods:

All 265 Hodgkin’s disease cases diagnosed at The Aga Khan University Hospital, Karachi over the last 6 years (July 1991 - July 1997) were included. Of these 219 were diagnosed on routine H&E examination while in the remaining 46 cases, diagnosis was made after a thorough IHC workup. (This group initially included 161 cases labelled as lymphoproliferative disorder with HD as one of …

Immunophenotypic Analysis Of Non-Hodgkin's Lymphoma, Suhail Muzaffar, Shahid Pervez, Farrukh Aijaz, Syed Abdul Aziz, Sheema H. Hasan

Department of Pathology and Laboratory Medicine

One hundred and three cases of Non-Hodgkin’s lymphoma were evaluated immunohistochemically using a panel of monoclonal antibodies which includes leucocyte common antigen (LCA), CD45R (Pan-B marker), L-26 (CD 20-Pan-B marker) and UCHL-1 (Pan-T marker). Of the total 63 cases (61.17%) showed a B-cell phenotype while 40(38.83%) were of T-cell origin. Most B-cell neoplasms belonged to intermediate (79.36%) or high grade (15.87%) according to the international Working Formulation (WF). Most T- cell lymphomas were of either intermediate (52.5%) or high grade (32.5%) neoplasms. Some T-cell neoplasms presented as specific clinicopathological entities like lymphomatoid granulomatosis (2 cases), mycosis fungoides (1 case) and …

Classification And Immunophenotyping Of Acute Leukemias: A Prospective Study., Shahid Pervez, M. Khurshid

Department of Pathology and Laboratory Medicine

Over a period of 3-1/2 years, 86 cases of acute leukemia were analyzed by immunohistochemical (IHC) means on ficoll separated cytospin preparations of peripheral blood and/or bone marrow samples. Antibodies included in the panel were specific against Tdt, HLA-DR, CD19/CD2O/CD22, CALLA (CD1O), CD2, CD11C as well as against Ig heavy chains. Of 86 cases analyzed, 48 cases were of ALL, (25 of common pre-B ALL, 15 of pre-B/NULL and 8 of T ALL phenotype), twenty-four (24) out of 86 cases were of non­lymphoblastic (AML/AMML) type. In six cases, there was suggestion of a mixed lineage, while in 8 cases there …

Localized Tuberculosis And Myelofibrosis With Myeloid Metaplasia : An Extremely Unusual Presentation, Suhail Muzaffar

Department of Pathology and Laboratory Medicine

Myelofibrosis with myeloid metaplasia (MMM) is usually considered primary agnogenic, however, it may be secondary to various diseases, The association of tuberculosis with MMIM is exceedingly rare, however, the pathogenetic relationship between the two is difficult to define. We present a case report showing simultaneous presentation of localized active tuberculosis and MMM The literature on the subject is also reviewed with special emphasis on pathogenic relation­ship between the two.