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Curt I Civin
 

Curt I Civin M.D.

Academic Title: Professor
Primary Appointment: Pediatrics
Secondary Appointments: Physiology
Additional Title(s): Director of the Center for Stem Cell Biology & Regenerative Medicine; Associate Dean for Research
ccivin@som.umaryland.edu
Location: BRB, 14-021; HSF II, S103D (lab)
Phone: (410) 706-1198
Phone: (410) 706-1181

Personal History:

Curt Civin MD serves as Associate Dean for Research, Director of the Center for Stem Cell Biology & Regenerative Medicine, and Professor of Pediatrics and Physiology in the University of Maryland School of Medicine. Civin discovered CD34+ lympho-hematopoietic stem-progenitor cells, opening entirely new directions in stem cell, leukemia, immunology and transplantation research. He developed the first successful stem cell therapy emanating from basic research, as proved in his own patients. CD34 was the first and is still the best marker for hematopoietic stem-progenitor cells.

Identification and isolation of CD34+ blood-forming stem-progenitor cells dramatically improved stem cell research and led to improved stem cell transplantation for thousands of patients. Dr. Civin studies the cell and molecular biology of the stem and progenitor cells that form the normal blood and immune systems, and the malignant counterparts of these stem-progenitor cells, the leukemias. Currently, Dr. Civin’s lab seeks to understand how the survival, proliferation, and differentiation of normal and malignant stem-progenitor cells are regulated. In basic studies, the Civin lab has comprehensively described protein-coding genes and microRNAs that are active in human hematopoietic stem-progenitor cells, using microarrays and amplification strategies. The lab's mission is to translate the resulting understanding and tools to clinical use.

In 1984, Curt Civin made the CD34 monoclonal antibody and identified CD34+ lympho-hematopoietic stem-progenitor cells, immediately opening entirely new directions in stem cell, leukemia, and transplantation research (Civin et al., J Immunol, 1984; Leary et al., J Clin Invest, 1984). His work led to the first successful approach emanating from basic molecular research into stem cell therapy, as Civin proved in his own patients. Civin then went on to immunophenotypically characterize most major stages and lineages of human blood and immune cell development from CD34+ progenitors (e.g. Loken et al., Blood, 1987), determine diagnostic-prognostic subtypes of leukemias (e.g. the CD34+CD38- subset which is highly enriched in engrafting human hematopoietic stem cells [Civin et al., Blood, 1996]), and discover key stem cell molecules (e.g. FLT3 receptor [Small et al., PNAS, 1994], KLF4 [Alder et al., J Immunol, 2008), microRNAs [Georgantas et al., PNAS, 2007], TTP [Kaplan et al., J Immunol, 2011]).

CD34 was the first and is still the best marker for identification of hematopoietic stem-progenitor cells, as well as endothelial cells and their progenitors. The CD34 monoclonal antibodies Civin developed have provided a highly efficient technology to immunoaffinity-purify these key cells. Over 25,000 scientific articles have been published involving CD34, and thousands of patients have received CD34+ cell transplants. The direct clinical impact of CD34 also includes many thousands of patients whose leukemias have been sub-classified using monoclonal antibody immunophenotyping panels and whose cytokine-mobilized peripheral blood stem cell harvests have been assessed for numbers of CD34+ hematopoietic stem-progenitor cells. These discoveries continue to guide the field of hematopoietic stem cell research and to provide a lasting impact on patient care.

Meanwhile in his own laboratory, Civin has gone on to further study the biology of the hematopoietic stem-progenitor cells he identified. Recently, the Civin laboratory profiled mRNA and microRNA expression in primary human CD34+ hematopoietic stem-progenitor cells and proposed (Georgantas et al., PNAS, 2007) a model wherein many of the mRNAs that specify hematopoietic differentiation are transcribed by hematopoietic stem-progenitor cells, but hematopoietic stem-progenitor cell differentiation is held in check post-transcriptionally by microRNAs. They also investigated microRNAs that they found downregulated in many leukemias, as compared to normal hematopoietic stem-progenitor cells or more mature hematopoietic cell types. (Re)expressing these downregulated microRNAs in leukemias led to reduced cell proliferation and increased apoptosis (Scheibner et al., PLOS ONE 2012). Indeed, the Civin lab and others have identified many microRNAs differentially expressed in normal versus leukemic cells, in the hopes of targeting such differences to selectively kill leukemic cells while sparing normal cells. However, expression analysis alone cannot distinguish the microRNAs driving leukemia from those associated with leukemia. Thus, the Civin lab developed a functional genomic screen to identify microRNAs with tumor suppressor activity (Cheng et al., BioTechniques, 2013).

As they considered the potential of these and other tumor suppressive microRNAs for antileukemic therapy, Civin realized that there is still no clearly effective means to deliver a variety of miRs to cancer cells at all sanctuary sites in the body and microRNAs are considered to be undruggable targets. Therefore, they attempted to discover small molecule compounds that selectively alter the levels of specific microRNAs in human cells. MiR-34, a paradigm tumor suppressor microRNA, is a key effector of the DNA damage response, and overexpression of miR-34a inhibits proliferation and survival of multiple cancers including leukemias. The Civin lab conducted an innovative high-throughput screen to identify clinically approved drugs that selectively upregulate miR-34 in a p53-negative leukemia cell line, with the goal of repurposing the best such drugs as leukemia therapeutics. Via this drug screen, they have found a set of drugs that selectively upregulate miR-34 and have been used in humans. This drug set includes the Artemisinins, a (low cost) drug class used widely for severe malaria with broad anti-cancer activity in preclinical studies. Artesunate has low clinical toxicity and is active against leukemia cell lines and primary human leukemia cases at low micromolar concentrations. The Civin lab very recently determined structure-activity relationships for 20 new dimeric Artemisinin analogs on growth of human acute leukemia cell lines, and they have found a highly potent analog called ART-838 that inhibits leukemia cell growth at nanomolar concentrations (Mott et al., Bioorg Med Chem, 2013) and has a high therapeutic index. In addition, they have found that mice tolerate high doses of ART-838, and that Artemisinins synergize with existing antileukemic drugs. The Civin lab is in the midst of experiments in vitro and in their primary xenograft model to determine predicted therapeutic indices for Artesunate and ART-838. Based on their preclinical results, they will design Phase I/II clinical trials to repurpose Artesunate and ART-838 for adult and childhood leukemia treatment and plan future Artemisinin-based successor clinical trials. They are also determining the mechanistic role of leukemia mutations, reactive oxygen species, and miR-34 in Artemisinin sensitivity in basic research studies. They hypothesize that Artesunate and ART-838 both have sufficient antileukemic potential to justify Phase I/II clinical trials in acute leukemias, and they further predict that Artesunate and/or ART-838, eventually in combination with current antileukemic drugs or other lead candidates from their screens, will improve the treatment of at least some subtypes of leukemia, and potentially other cancers. The clinical success of their research would validate the idea of discovering drugs that upregulate tumor suppressor microRNAs as an effective new strategy for antineoplastic drug development.

Discoveries are just one category of product of Civin’s >30 year cancer research career. Civin has also built outstanding programs (Johns Hopkins Division of Pediatric Oncology, University of Maryland Center for Stem Cell Biology & Regenerative Medicine), and via these programs, he has inspired many highly talented trainees in cancer and stem cell research and served as a direct laboratory research mentor to several leading cancer researchers (e.g. Professors Kastan, Small, Gore, Mirro, Schwartz, Wiley, Friedman, Leung).

Civin has also been a tireless and highly effective public advocate for childhood cancer, cancer/leukemia, transplantation, stem cell and regenerative medicine research, and translational biomedical research. His testimony on the importance of human embryonic stem cell research in the US Senate and Maryland House of Delegates is always scholarly but clear and to-the-point. His advocacy efforts led to the thriving Stem Cell Research Fund in the State of Maryland. Civin is both an inventor and chaired for a decade the Johns Hopkins Committee on Conflicts of Interest, and has spoken on the difficult regulation of these related areas. Similarly, he weaves together medicine and science and exemplifies the physician-scientist. Over his long career, Civin has led in every aspect of academic biomedicine, and he brings his abundant talents to academic missions enthusiastically.

OTHER INFORMATION

  • Associate Dean for Research, University of Maryland School of Medicine
  • Director, Center for Stem Cell Biology & Regenerative Medicine, UMSOM
  • Professor, Departments of Pediatrics and Physiology, UMSOM
  • Member, UM Greenebaum Cancer Center
  • Member, UM Center for Biologic Therapies

Principal Previous Positions Held:

  • Investigator, Pediatric Oncology Branch, National Cancer Institute/NIH, 1978-1979
  • Assistant Professor, Associate Professor, Professor, King Fahd Professor, Herman & Walter Samuelson Professor; Depts of Oncology & Pediatrics, Johns Hopkins University School of Medicine, 1979-2009 (Adjunct Professor, 2009-pres)
  • Director, Pediatric Oncology Division, JHUSM, 1984-2000                            
  • Co-Director, Immunology & Hematopoiesis Division, JHUSM, 2000-2009
  • Adjunct Senior Investigator, Pediatric Oncology Branch, Division of Clinical Sciences, National Cancer Institute, 2000-pres

Education:

  • BA, magna cum laude, Biology/Independent Study, Amherst College, Amherst, MA, 1966-70
  • MD, cum laude, Harvard Medical School, Boston, MA, 1970-74
  • Pediatric Residency, Children’s Hospital Medical Center, Boston, MA, 1974-76
  • Fellowship in Pediatric Hematology-Oncology, National Cancer Institute, Bethesda, MD, 1976-79
  • ScD (honorary), Amherst College, Amherst, MA, 2001

National Leadership Positions:

  • Editorial Boards: Experimental Hematology, 1986-89; Hematologic Pathology, 1987-96; Blood, 1988-92; Editorial Board, Journal of Hematotherapy, 1992-99; Oncology News International, 1992-2004; Communications in Clinical Cytometry, 1993-98; Clinical Cancer Research, 1994-2001; Cell Transplantation, 1995-98; Stem Cells, 1994-96, 1998-2008 (Assoc Editor, 1998-2000; Editor-in-Chief, 2000-08)
  • Young Investigators Award Selection Committee, American Society of Clinical Oncology, 1989-93 (1991-92, Chair)
  • Program Committees: Multiple, including American Society of Hematology, American Society of Clinical Oncology, American Association for Cancer Research
  • Medical/Scientific Advisory Boards (national, nonprofit): Sidney Kimmel Foundation for Cancer Research, 1996-pres; Gabrielle’s Angels (formerly G&P Charitable Foundation For Cancer Research), 1999-pres; Leukemia Lymphoma Society, 1999-pres (Co-Chair, 2010-pres)
  • Member, Subcommittee D (Translational Studies), National Cancer Institute Initial Review Group, 2005-2007
  • Chair, Career Development Program, Clinical Scholar & Fellow Awards, Leukemia & Lymphoma Society, 2007-2010
  • Member, National Cancer Institute Board of Scientific Advisors (BSA), 2007-2015
  • Member, National Cancer Institute Clinical Trials Advisory Committee (CTAC), 2008-2015

Research Interests:

Curt Civin’s breakthrough discovery of the CD34 lympho-hematopoietic stem cell antigen and monoclonal antibody has facilitated basic research in stem cell biology and leukemia and has led to improved stem cell transplantation for thousands of patients. These discoveries have led to multiple honors for Civin, including the 1999 National Inventor of the Year Award and the 2009 Karl Landsteiner Award. Civin built a leading Pediatric Oncology division at Johns Hopkins and inspired an exceptional number of talented trainees to pursue careers in translational research. While now expanding his impact on the next generation of physician-scientists at the University of Maryland School of Medicine Center for Stem Cell Biology & Regenerative Medicine, Civin’s own research focuses on the roles of key molecules, especially microRNAs, in normal and leukemic stem-progenitor cells.


D. Research Support:

Ongoing Research Support

TRP#285855

Leukemia & Lymphoma Society

Civin (PI)

10/1/13-09/30/16

Translational Research Award: Artemisinins for treatment of acute leukemias

Compare Artesunate vs Artemisinin-derived-dimer-838 for effects on growth of primary human acute myeloid leukemia cases and normal hematopoietic stem-progenitor cells, using in vitro and in vivo assays.


No number 

National Foundation for Cancer Research

Civin (PI)

01/01/14 - 12/31/16

NFCR Fellow Award

Support general laboratory infrastructure and specific research not specifically funded by any other source.


No Number

William Lawrence & Blanche Hughes Foundation

Chen (PI)

12/1/13 - 11/30/14

Preclinical development of Artemisinins for treatment of childhood acute lymphoblastic leukemias

Determine the efficacy of Artesunate and the potent ART-838 analog against childhood acute lymphoblastic leukemias in vitro and in vivo, as well as toxicity to normal human hematopoietic stem-progenitor cells. Role: Investigator


2010-MSCRFII-0065

MSCRF/TEDCO        

Civin (PI)

06/30/10-06/29/15

Hematopoietic stem cell-enriched microRNAs in human stem cell differentiation and self-renewal

Understand the effects of Hematopoietic Expressed-miRs in early hematopoiesis.


R41HL110574

NIH/NHLBI

Civin/Sturm (Multi-PI/PD)

08/01/12-04/30/14

STTR: High Efficiency Microfluidic Purification of Stem Cells to Improve Transplants

Effectively deplete erythrocytes and recover leukocytes from cord blood via microfluidic chips.


R41CA174121      

NIH/NCI

Civin/Sturm (Multi-PI/PD)

09/24/12-08/31/14

STTR: Microfluidic Processing of Leukocytes for Molecular Diagnostic Testing

Modify deterministic lateral displacement microfluidic technology to replace Wash/Concentrate Steps in leukocyte processing.


2012-MSCRFE-0272

MSCRF/TEDCO

Kingsbury (PI)

06/30/12-06/29/14

MicroRNAs and control of quiescence and pluripotency

Identify microRNAs whose enforced expression reduces hematopoietic stem-progenitor cell ROS.
Role: Investigator


2012-MSCRFE-0244

MSCRF/TEDCO

Scheibner (PI)

06/30/12-06/29/14

Regulation of DNA double strand break repair in human hematopoietic stem cells by microRNAs

Identify specific miRs regulated by radiation, and to determine if radiation-regulated miRs regulate DSB repair in hHSPCs. Role: Investigator


T32CA154274 

NIH/NCI

Antalis/Civin (Multi-PI/PD)

07/01/11-06/30/16           

Training Grant in Cancer Biology

Create a new program in Integrative Cancer Biology to train post-doctoral and pre-doctoral trainees committed to careers in cancer research.


U01FD004320

FDA

Bentley/Polli (Multi-PI/PD)

09/15/11-09/14/14

University of Maryland Center of Excellence in Regulatory Science and Innovation

Supports a Collaborating Center of Excellence in Regulatory Science and Innovation (CERSI) in the national capital region. Role: Investigator


2012-MSCRFE-0081

MSCRF/TEDCO

Zhan (PI)

06/30/12-06/29/14

Modulation of homing and engraftment of hematopoietic stem cells by I-BAR proteins
Characterize the role of MIM gene in human HSPC homing, engraftment and mobilization, and develop small molecules targeting MIM dimerization. Role: Investigator


K08HL097069

NIH/NHLBI

Kaushal (PI)

09/1/09-5/31/14

Mentored Clinical Scientist Development Award: Characterization of Cell-Based Therapy for Congenital Heart Patients
Characterize endogenous cardiac stem cells from the mouse and congenital heart patients to recover a doxorubicin induced cardiomyopathy model.  Role: Mentor


2013-MSCRFII-0158

MSCRF-TEDCO

Kaushal (PI)

06/01/13–05/30/16

Characterization of Cardiac Stem Cells in Neonates
Characterize endogenous cardiac stem cells from neonates. Role: Investigator


R01 HL118491

NIH/NHLBI

Kaushal (PI)

04/1/14 - 03/31/19

Biological Characterization of Cardiac Stem Cells
Better understand mechanisms by which resident cardiac stem cells exert their functional activity.
Role: Investigator


K08HL93207

NIH/NHLBI

Banerjee (PI)

09/1/10–5/31/15

Mentored Clinical Scientist Development Award: Transcriptional Regulation of CD8+ T Cell Differentiation
Determine the roles of T-bet and Eomesodermin in CD8+ T cell subset differentiation during anti-tumor immune responses. Role: Mentor


Publications:

Key Publications:

Alder JK, Georgantas RW, Hildreth RL, Kaplan IM, Morisot S, Yu X, McDevitt M, Civin CI. Kruppel-like factor 4 is essential for inflammatory monocyte differentiation in vivo. J Immunol 2008;180:5645-5652.

Chu SH, Heiser D, Li L, Kaplan I, Collector M, Huso D, Sharkis SJ, Civin CI, Small D. FLT3-ITD knockin impairs hematopoietic stem cell quiescence/homeostasis, leading to myeloproliferative neoplasm. Cell Stem Cell 2012;11:346-358.

Cheng WC, Kingsbury TJ, Wheelan SJ, Civin CI. A simple high-throughput technology enables gain-of-function screening of human microRNAs. BioTechniques 2013;54:77-86.

Civin CI, Strauss LC, Brovall C, Fackler MJ, Schwartz JF, Shaper JH. Antigenic Analysis of Hematopoiesis III.  A Hematopoietic Progenitor Cell Surface Antigen Defined by a Monoclonal Antibody Raised Against KG–1a Cells.  J Immunol 1984;133:157–165.

Civin CI, Trischmann T, Kadan NS, Davis J, Noga S, Cohen K, Duffy B, Groenewegen I, Wiley J, Law P, Hardwick A, Oldham F, Gee A. Highly Purified CD34+ Cells Reconstitute Hematopoiesis. J Clin Oncol 1996;14:2224-2233.

Civin CI, Almeida-Porada G, Lee M-J, Olweus J, Terstappen LWMM, Zanjani ED. Sustained, retransplantable, multilineage engraftment of highly purified adult human bone marrow stem cells in vivo. Blood 1996;88:4102-4109.

Georgantas RW, Tanavde V, Malehorn M, Heimfeld S, Chen C, Carr L, Murillo F, Riggins G, Civin CI. Microarray and SAGE analyses identify known and novel transcripts over-expressed in hematopoietic stem cells. Cancer Res 2004;64:4434-4441.

Cramer K., Nieborowska-Skorska M., Scheibner K., Padget M., Irvine D., Sliwinski T., Haas K., Lee J., Roy D., Slupianek A., Waski M., Childers W., Copland M., Muschen M., Civin C.I., Skorski T. Personalized  Synthetic Lethality Induced by Targeting RAD52  in Leukemias Identified by Gene Mutation and Expression Profile. Blood 122:1293-304, 2013.  PMID: 23836560 PMCID:  PMC3744994

Georgantas RW, Hildreth R, Morisot S, Alder J, Liu CG, Heimfeld S, Calin GA, Croce CM, Civin CI. CD34+ hematopoietic stem-progenitor cell microRNA expression and function. A circuit diagram of differentiation control. Proc Natl Acad Sci 2007;104:2750-2755.

Godsey B, Heiser D, Civin CI. Inferring MicroRNA Regulation of mRNA with Partially Ordered Samples of Paired Expression Data and Exogenous Prediction Algorithms. PLOS ONE 2012; 7:e51480.

Heiser D., Tan Y.S., Kaplan I., Godsey B., Morisot S., Cheng, W.C., Small D., Civin C.I. Correlated miR-mRNA expression signatures of mouse hematopoietic stem and progenitor cell subsets predict “stemness” and “myeloid” interaction networks, PLoS One 2014, In Press, EMID:73776ab888c89876.

Huang CRL, Schneider AM, Yunqi L, Tejasvi N, Peilin S, Robinson M, Steranka J, Valle D, Civin CI, Wang T, Wheelan S, Ji H, Boeke J, Burns KH. Mobile Interspersed repeats are major structural variants in the human genome. Cell 2010;141:1171-1182.

Kaplan I, Morisot S, Heiser D, Cheng WC, Kim MJ, Civin, CI. Deletion of Tristetraprolin (TTP) caused spontaneous reactive granulopoiesis by a non-cell autonomous mechanism without disturbing LT-HSC quiescence. J Immunol 2011;1865:2826-2834.

Leary AG, Ogawa M, Strauss, LC, Civin CI. Single Cell Origin of Multilineage Colonies in Culture: Evidence that Differentiation of Multipotent Progenitors and Restriction of Proliferative Potential of Monopotent Progenitors are Stochastic Processes. J Clin Invest 1984;74:2193-2197.

Loken MR, Shah VO, Dattilio KL, Civin, CI. Flow Cytometric Analysis of Human Bone Marrow. II. Normal B Lymphocyte Development.  Blood 1987;70:1316-1324.

Morisot S, Wayne AS, Bohana-Kashtan O, Kaplan IM, Gocke CD, Hildreth R, Stetler-Stevenson M, Walker RL, Davis S, Meltzer PS, Wheelan SJ, Brown P, Jones RJ, Shultz LD, Civin CI. High Frequencies of Leukemia Stem Cells in Poor Outcome Childhood Precursor B Acute Lymphoblastic Leukemias. Leukemia 2010;11:1859-1866.

Mott BT, He R, Chen X, Fox JM, Civin CI, Arav-Boger R, Posner GH. Artemisinin-Derived Dimer Phosphate Esters as Potent Anti-Cytomegalovirus (Anti-CMV) and Anti-Cancer Agents: A Structure-Activity Study. Bioorg Med Chem 2013, In Press.

Sharkis SJ, Jones RJ, Civin CI, Jang YY. Pluripotent Stem Cell-Based Cancer Therapy: Promise and Challenges. Sci Transl Med 2012; 4:127.

Scheibner KA, Teaboldt B, Hauer MC, Chen X, Cherukuri S, Guo Y, Kelley SM, Liu Z, Baer MR, Heimfeld S, Civin CI. MiR-27a Functions as a Tumor Suppressor in Acute Leukemia by Regulating 14-3-3theta. PLOS ONE 2012;7:e50895.

Small D, Levenstein M, Kim E, Carow C, Amin S, Rockwell P, Witte L, Burrow C, Ratajczak M, Gewirtz A, Civin CI. STK–1, The Human Homolog of Flk–2/Flt–3, is Selectively Expressed in CD34+ Human Bone Marrow Cells and is Involved in the Proliferation of Early Progenitor/Stem Cells. Proc Natl Acad Sci 1994;91:459–463.

Zambidis ET, Peault B, Park TS, Bunz F, Civin CI. Hematopoietic differentiation of human embryonic stem cells progresses through sequential hemato-endothelial, primitive, and definitive stages resembling human yolk sac development. Blood 2005;206:860-870.