2008-12-06

The ASH Scholar Awards are highly competitive grants that provide partial salary support during the transitional period between completion of training and achievement of status as an independent investigator. The goal of the program is to encourage beginning hematologists to pursue a research career in either basic or clinical/translational research. ASH News Daily is proud to feature profiles of some of the current class of scholars in each issue of the paper at this year’s annual meeting.

Larry D. Bozulic, PhD, a Basic Research Fellow Scholar, is currently a postdoctoral research associate looking forward to becoming an independent tenure-track faculty member at the University of Louisville. This fellowship is the next step in moving his career toward a tenure-track position. His new focus on transplantation immunology and stem cell biology has sparked considerable interest in understanding the biological aspects of mixed chimerism and the signal transduction mechanisms responsible for induction of tolerance. Mixed chimerism reverses the active autoimmunity in prediabetic mice and humans and induces tolerance to transplanted islets. His project focuses on developing a novel approach to condition autoimmune non-obese diabetic mouse recipients for engraftment and to determine whether conditioned chimeras are functionally tolerant to islet allografts. Moreover, he will determine whether this novel conditioning approach generates regulatory T cells known to play a key role in maintaining tolerance to alloantigens in vivo. These mechanisms may be critical in understanding the underlying autoimmunity that destroys transplanted b-islet cells and may aid in promoting the acceptance of functional b-cell mass. Dr. Bozulic’s new focus will afford him the opportunity to answer many challenging issues facing this exciting field. He looks forward to the stimulating knowledge, development of new strategies, and discussion of leading-edge science among other scientific researchers.

Jalila Chagraoui, PhD, a Basic Research Fellow Scholar, earned her PhD in France, where she studied the hematopoietic supportive microenvironment and extrinsic factors regulating hematopoietic stem cells (HSCs), particularly in the fetal liver known as the major hematopoietic site during embryonic and fetal life. To complete these graduate studies, she aims to continue her training in the study of the intrinsic determinants influencing the self-renewal/differentiation ability of HSCs. Her ultimate goal is to become an independent researcher in this field.

For these reasons, Dr. Chagraoui initiated a postdoctoral formation four years ago in Dr. Sauvageau’s laboratory, which offers an exceptional environment to gain the knowledge and background required to continue her education. Dr. Sauvageau is well known for his work in the field of HSCs and the involvement of intrinsic factors, such as Hox and polycomb genes, in the regulation of HSC behavior. There, she had the opportunity to work on Bmi1, a polycomb group gene shown to be essential for both normal and leukemic stem cell self-renewal, and she recently published a paper in Genes and Development on the genetic interaction between Bmi1 and E4F1, a negative regulator of cell proliferation. Dr. Chagraoui is now focusing her studies on the mechanisms underlying Bmi1 function in HSCs.

Francesca Ficara, PhD, a Basic Research FellowScholar, received her degree in biological sciences in 1998 from the University of Milano, Italy, and her PhD in immunological sciences in 2003 from the University of Ancona, Italy. She conducted her studies on gene therapy for ADA-SCID immunodeficiency in Prof. Aiuti’s laboratory at the San Raffaele Telethon Institute for Gene Therapy in Milan until 2004, when she joined Prof. Cleary’s laboratory at Stanford University. The ASH Scholar Award is supporting her research aimed at characterizing the physiological role of Pbx1 transcription factor in the hematopoietic system. Pbx1 was originally discovered in the host laboratory as a proto-oncogene leading to acute lymphoblastic leukemia when involved in chromosomal translocations. Pbx1 deficiency severely affects definitive hematopoiesis in the embryo; however, its role in the adult hematopoietic stem cell (HSC) compartment was unknown. In her current study, Dr. Ficara conditionally inactivated Pbx1 in the mouse hematopoietic system in vivo. In contrast to its previously described role in promoting progenitor expansion, Dr. Ficara discovered that Pbx1 positively regulates HSC quiescence. Her studies (published in Cell Stem Cell) demonstrate that Pbx1 is a novel regulator of HSC self-renewal that contributes to maintenance of HSC quiescence as an essential component of cellular response to Tgf-b signaling.

Maria Figueroa, MD, a Basic Research Fellow Scholar, graduated from Universidad del Salvador’s School of Medicine in Buenos Aires, Argentina, in 1997, and went on to complete her residency in internal medicine. She received her hematology training at the Institute for Hematological Research "Mariano Castex" (IIHEMA) in 2002, where she later worked as a clinician for two more years in the Oncology/Hematology Department. During that time, Dr. Figueroa be-came increasingly interested in the molecular pathogenesis of leukemias. She joined Dr. Ari Melnick’s lab at the Albert Einstein College of Medicine in 2004, where she has worked in the field of leukemia epigenetics. Specifically, they are interested in decoding the genetic and epigenetic circuitry of leukemia and MDS patients in order to better understand disease pathophysiology, achieve a more accurate biological classification, and develop more effective targeted therapeutic regimens. For this they have developed an integrated genomic and epigenomic microarray platform in which they combine the power of gene expression arrays with genome-wide studies of DNA methylation and histone modifications, and use the integrated information to broaden their biological understanding of these diseases.

Paul Galardy, MD,Basic Research Junior Faculty Scholar, earned his MD from Boston University School of Medicine and received training in pediatrics and pediatric hematology/oncology at Harvard Medical School. Following his clinical training, Dr. Galardy worked in the laboratory of Hidde Ploegh, PhD, (Whitehead Institute) on the development and application of activity-based probes for analyzing the UPS in hematologic malignancies. This work led to a detailed model of the interaction of the drug bortezomib with the catalytic subunits of the proteasome in living cells. Through collaboration with Alan D’Andrea, MD (Dana-Farber Cancer Institute), Dr. Galardy helped to elucidate the role of de-ubiquitination as a regulatory step in the Fanconi anemia pathway. He currently is an assistant professor in the Departments of Pediatrics and Biochemistry & Molecular Biology at the Mayo Clinic, Rochester, MN. He is continuing to study the role of the UPS in malignancy through the generation of transgenic and knockout mouse models of tumorigenesis focusing on the family of enzymes known as de-ubiquitinases. These enzymes, which counteract the addition of ubiquitin onto protein substrates, are thought to play important regulatory roles in many aspects of normal and malignant cell biology.

Hanno Hock, MD, PhD,a Basic Research Junior Faculty Scholar, is a hematologist/oncologist from the Massachusetts General Hospital Cancer Center and Center for Regenerative Medicine in Boston. He is an assistant professor of medicine at Harvard Medical School and a member of the Harvard Stem Cell Institute. Dr. Hock originally studied medicine and immunology in Germany at the Free University of Berlin. He did his residency in internal medicine at Beth Israel Medical Center in New York and completed a fellowship in hematology and oncology in the Dana-Farber/Partners program in Boston. After postdoctoral work with Dr. Stuart Orkin at Children’s Hospital, Dr. Hock started his own laboratory at the Massachusetts General Hospital in 2005. Dr. Hock’s laboratory is interested in the transcriptional regulation of stem cells in normal blood development and leukemia. Using genetically engineered mouse strains, his lab investigates how key transcription factors maintain stem cells in the bone marrow, how key transcription factors establish differentiation specific transcriptional programs, and how abnormal transcription factors derail these processes to allow for the development of leukemia. The lab’s major emphasis is on three transcription factors: the Ets-related transcription factor Tel/Etv6 and the zinc-finger transcription factor Gfi-1 (both critical for maintaining HSCs in the bone marrow), as well as the leukemia translocation-associated hybrid transcription factor Tel-Aml.

Hanna K.A. Mikkola, MD, PhD, a Basic Research Junior Faculty Scholar, is assistant professor in the Department of Molecular, Cell and Developmental Biology and Eli and Edythe Broad Center for Stem Cell Research and Regenerative Medicineat the University of California, Los Angeles. Dr. Mikkola received her MD and PhD in 1997 from the University of Helsinki, Finland. She did her PhD thesis work with Aarno Palotie and Leena Peltonen-Palotie on defining genetic defects in a congenital bleeding disorder, factor XIII deficiency. She became interested in hematopoietic stem cells (HSCs) during her postdoctoral training in Stefan Karlsson’s laboratory in Lund, Sweden, where she developed lentiviral gene transfer systems to manipulate stem cells. In 2000, Dr. Mikkola joined Stuart Orkin’s lab at the Dana-Farber Cancer Institute, Harvard Medical School, in Boston. She focused on transcriptional regulation of HSCs and defining their origin and discovered that the placenta is an important hematopoietic organ that supports HSC development. Dr. Mikkola started her own research group at UCLA in 2005 and continues to investigate how HSCs develop during embryogenesis in mice and humans, with special emphasis on exploring the hematopoietic microenvironment in the placenta and on defining the nuclear regulatory mechanisms that distinguish self-renewing HSCs from transient hematopoietic progenitors.

David Miklos, MD, PhD, a Clinical/Translational Research Junior Faculty Scholar, is an HCT clinician who specializes in non-myeloablative allogeneic transplant treatment of B-cell malignancies while his laboratory studies B-cell reconstitution, especially the role of allogeneic B-cell immunity in graft-versus-tumor and graft-versus-host disease (GVHD). He graduated from the University of Notre Dame and earned his MD/PhD from Yale University. His initial HCT research demonstrated that allogeneic antibodies develop against H-Y antigens in association with chronic GVHD (cGVHD) following sex-mismatched transplantation and suggested anti-B-cell drugs for cGVHD. Subsequent clinical trials have shown rituximab to be an effective and safe cGVHD therapy. Dr. Miklos, his wife, Shalina, and their two children moved to Stanford in 2004. His lab has developed microarray technology to identify human protein targets of allo-antibodies, and this immunogenomic research is defining their role as tumor antigens and minor histocompatibility antigens. His allotype studies distinguishing antibodies as donor- or recipient-derived shows that persistent recipient humoral immunity dominates for at least a year after HCT. This year at the annual meeting, Dr. Miklos’ lab reports a clinical trial of rituximab infused two months after reduced-intensity-conditioning allogeneic HCT results in significantly less cGVHD and delayed serologic alloimunity. His laboratory characterizes B-cell reconstitution following allo-HCT by multi-dimension FACS bone marrow analysis and serologic allotype assays that distinguish donor and recipient antibodies that provide antimicrobial, alloreactive, and autoimmune serologic immunity.

Sattva Neelapu, MD, a Clinical/Translational Junior Faculty Scholar, completed his clinical fellowship in medical oncology and laboratory research training in tumor immunology and immunotherapy at the National Cancer Institute, National Institutes of Health. In 2004, he joined the Department of Lymphoma and Myeloma as an assistant professor at The University of Texas M. D. Anderson Cancer Center. At NCI, he was involved in the development of therapeutic idiotype vaccines for patients with lymphoma and myeloma under the mentorship of Dr. Larry Kwak. Although idiotype vaccines were shown to be immunogenic and results from early-phase clinical trials were encouraging, Dr. Neelapu recognized that progress in the development of active immunotherapeutic strategies for lymphoma may be hindered by the need to generate a custom-made idiotype vaccine product for each patient. His laboratory is now focused on the identification of novel, shared tumor-associated antigens that can be used universally in patients with lymphoma. In addition, Dr. Neelapu is characterizing the immunoregulatory mechanisms in the lymphoma tumor microenvironment. Dr. Neelapu’s research is supported by the American Society of Hematology, the American Society of Clinical Oncology, NIH, and the Doris Duke Charitable Foundation.

Emmanuelle A. Passegué, PhD, a Basic Research Junior Faculty Scholar, is an assistant professor in the Department of Medicine with the Institute for Regeneration Medicine (IRM) at the University of California San Francisco (UCSF). Her research focuses on deciphering the mechanisms controlling hematopoietic stem cells (HSCs) and progenitor cell functions during normal hematopoiesis and in hematologic malignancies. In particular, she is using mouse models of myeloid leukemia to investigate leukemia-initiating stem cell (LSC) formation and function. Dr. Passegué’s current studies center on understanding the fundamental properties of the HSC compartment that can be co-opted by oncogenic events to either directly transform HSCs or provide aberrant self-renewal activity to more committed cells. Her recent work also studies the implication of proliferation, apoptosis, and DNA repair mechanisms in maintenance and regulation of HSCs and LSCs in murine models. Dr. Passegué’s work is expanding our understanding of the biology of normal and leukemic stem cells and could lead to new treatment for human hematologic malignancies.

Dr. Passegué earned her PhD from the University Paris XI, France. She first trained as a mouse geneticist at the Institute for Molecular pathology (IMP) in Vienna, Austria, where she worked with Dr. Erwin Wagner, and then as a stem cell biologist at Stanford University, where she worked with Dr. Irving Weissman. She joined the UCSF faculty in 2006.

Tobias Ragoczy, PhD, Basic Research Fellow Scholar, was born in Germany and has lived and studied in Europe and the United States. He obtained his BS in biochemistry at the University of St. Andrews in Scotland and his PhD in molecular biophysics & biochemistry from Yale University. During his graduate studies, Dr. Ragoczy investigated the regulation and function of the Epstein-Barr Virus Rta protein, an immediate-early transactivator, in the activation of the viral lytic cycle, in the laboratory of Dr. George Miller. He became interested in the role of chromatin in gene regulation and decided to tackle this question as a postdoctoral fellow in the laboratory of Dr. Mark Groudine at the Fred Hutchinson Cancer Research Center in Seattle. During his postdoctoral research, Dr. Ragoczy began to appreciate that beyond chromatin, the spatial organization of the cell nucleus exerts significant control over gene regulation and mis-regulation, and, consequently, his work has become more cell biology-oriented. Using the regulation of the murine b-globin locus during erythropoiesis as a model system, he is currently investigating the nuclear sub-compartments in which the locus is positioned during differentiation, and how this localization correlates with gene activity.

Dan Vogl, MD,a Clinical/Translational Research Fellow Scholar, is an assistant professor in the Bone Marrow Transplant and Hematologic Malignancies Program at the Abramson Cancer Center of the University of Pennsylvania. His clinical focus is on the therapy of plasma cell malignancies, including myeloma and amyloidosis. Current research interests include optimization of high-dose melphalan autologous transplants by understanding the impact of renal function and obesity on chemotherapy pharmacokinetics and outcomes, and improvement of bortezomib efficacy by inhibition of the aggresome-autophagy pathway. His research is funded by the American Society of Hematology Scholar Award and a Special Fellow in Clinical Research Award from the Leukemia and Lymphoma Society.

John B, Walker, PhD, a Basic Research Fellow Scholar, received his undergraduate and graduate degrees in biochemistry at Queen’s University in Kingston, Ontario, Canada. Dr. Walker did his graduate work with Mike Nesheim, characterizing plasmin-mediated fibrin degradation and investigating the plasminogen-activating cofactor activity of fibrin degradation products. He received a Heart and Stroke Foundation Postdoctoral Fellowship to pursue studies on thrombin-activable fibrinolysis inhibitor (TAFI) with Laszlo Bajzar at McMaster University (Hamilton, Ontario, Canada) where he was awarded a Young Investigator Award from the Canadian Society of Arterial Sclerosis, Thrombosis, and Vascular Biology, and a Young Investigator Excellence Award from the International Society for Fibrinolysis and Proteolysis. His current project focuses on identifying and purifying the factors present in plasma that inhibit the intrinsic antifibrinolytic activity of the constitutively active carboxypeptidase N (CPN), which, in contrast to its apparent lack of antifibrinolytic activity in plasma, can completely stop the lysis of clots formed using purified proteins. This work will form the foundation for studying the (patho)physiological effects of CPN on fibrinolysis and its relationship to disease states involving chronic antifibrinolysis. Dr. Walker is currently a research associate at the University of Alberta in Edmonton, Alberta, Canada, where he lives with his wife and two children.

back to top