Hematopoietic and Cancer Stem Cell Working Group
Stem cells hold great promise for regenerative medicine, but their clinical application is limited by our inability to expand them ex vivo (outside the body). Thus, ex vivo stem cell expansion has been referred to as a holy grail for research. Several University of Maryland faculty in the Hematopoietic and Cancer Stem Cell Working Group are working to discover and develop understanding and technologies necessary to expand hematopoietic stem cells for transplantation, as well as to produce in quantity specific cell types such as red blood cells, platelets, and granulocytes needed for blood transfusions. Others members of this Working Group are investigating the role of cancer stem cells in cancer development, progression and metastasis, in order to develop improved therapeutic strategies to prevent cancer recurrence.
This Working Group studies the biology and applications of hematopoietic (blood-forming) stem cells and also seeks to learn how to better eradicate cancer stem cells, using novel drugs and immunotherapy. Laboratory and clinical research, including clinical trials, on hematopoietic stem cell transplantation (also known as bone marrow transplantation) is included in this Working Group.
The Banerjee lab is investigating the mechanisms by which T-box family transcription factors regulate cell fate decisions in T lymphocytes and hematopoietic stem-progenitor cells. Their ongoing work in the role of T-box factors in T cell-based immunotherapeutic agents currently in clinical development will serve as a knowledge base to guide both the optimal use of these agents and the development of novel agents. Dr. Banerjee’s group is establishing a novel and critical role for T-box transcription factors in the differentiation of platelets and red blood cells from hematopoietic stem-progenitor cells with the long-term goal of developing a strategy to generate clinically relevant quantities of these blood products in vitro.
Banerjee, A., Gordon, S.M., Intlekofer, A.M., Paley, M.A., Mooney, E.C.,Lindsten T., Wherry, E.J., and Reiner, S.L.: The Transcription Factor Eomesodermin Enables CD8+ T Cells to Compete for the Memory Cell Niche. The Journal of Immunology 185, 4988-4992, (2010).
Dr. Kingsbury’s lab is investigating the role of microRNAs in the regulation of certain key hematopoietic stem-progenitor cell properties. MicroRNAs have recently emerged as critical regulators of gene expression with tantalizing therapeutic potential. This research takes advantage of a high throughput microRNA library screening platform technology developed in the Center for Stem Cell Biology & Regenerative Medicine to identify microRNAs that regulate a given function, such as cellular self-renewal. The goal of this research is to investigate mechanisms that regulate cardinal stem cell properties and to address pragmatic goals, such as enhancing expansion of high-quality hematopoietic stem cells ex vivo for use in bone marrow transplants.
Maria Baer is the Director of the Hematologic Malignancies program. Her laboratory research interests are in understanding molecular mechanisms mediating resistance of leukemia cells and stem cells to chemotherapy and developing approaches to overcoming chemoresistance that can be readily moved into the clinic. A current focus is inhibition of Pim kinases as an approach to chemosensitization. Dr. Baer leads clinical trials to test strategies to enhance chemotherapy efficacy in leukemias and target leukemia stem cells.
The lab of Dr. Bromberg has been involved continuously in basic cellular and molecular transplant immunology for over 23 years staying consistently funded. Their basic research has always focused on T cell immunobiology, and for more than 10 years has also focused on issues of migration, trafficking, secondary lymphoid organ structure and function, and lymphatic structure and function and how these processes and structures influence T cell immunity and T cell tolerance in models of cardiac transplantation, islet transplantation, and diabetes. Dr. Bromberg have also maintained an active clinical practice in solid organ transplantation and am thus has been constantly exposed to the problems of patients and their immune systems, including cellular and transplant rejection, opportunistic infections, chronic viral disease, autoimmune organ failure, and immunosuppressant medication side effects. His basic research and clinical interests are especially well suited to complement and inform each other, and to keep each aspect of his professional life current and relevant.
Dr. Chen’s lab is discovering and using chemical, biological and genetic tools to identify and manipulate signaling pathways that regulate normal hematopoietic stem-progenitor cell and leukemia stem cell survival, proliferation, and differentiation. In so doing, they propose to discover new drugs that can be used to expand normal hematopoietic stem-progenitor cells or inhibit leukemias. Ongoing projects include developing drugs and mechanisms that Dr. Chen has found to elevate the levels of tumor suppressor microRNAs and kill leukemia cells in both in vitro cell cultures and in vivo human-mouse chimera models.
Dr. Civin’s lab has identified a set of microRNAs that are differentially expressed in normal hematopoietic stem-progenitor cells as compared to leukemia cells, and he collaborates closely with Drs. Xiaochun Chen, Wen-Chih Cheng, Tami Kingsbury and Kara Scheibner. Research achievements include determining the functional roles and mechanisms of selected microRNAs that are down-regulated in human acute leukemias, engineering human leukemia cell lines to sense and report the intracellular concentrations of a given tumor suppressor microRNAs, and conducting high-throughput screens for small molecule compounds that selectively elevate the levels of that given microRNA. He also has collaborated to develop a novel and powerful functional screen termed “miR-HTS” that has been used to identify more than 20 microRNAs that regulate cell growth and other functions. The most interesting of these regulatory microRNAs are now being validated for effects on normal human hematopoietic stem-progenitor cells and leukemias. Finally, Dr. Civin is collaborating with engineers and physicists, along with a small company, to develop microfluidic chips that can quickly and efficiently separate blood cell types for research and clinical diagnostic and therapeutic use.
Dr. Feldman’s lab is using induced pluripotent stem cell reprogramming technology to model lipid storage disease. Dr. Feldman has developed the first disease-in-a-dish models for all 3 clinical subtypes of Gaucher disease, and has shown the utility of using induced pluripotent stem cell-based assays for drug discovery, by recapitulating the known therapeutic efficacies of current treatments. These discoveries are the result of a multi-institutional collaboration involving investigators at UM, Johns Hopkins, and the National Institute of Health (NIH).
Dr. Hamburger’s laboratory is interested in the role of ErbB family members in the generation of breast cancer stem cells. In a collaboration with Drs. Ross and Burger, they have showed that enforced expression of ErbB2 in luminal primary breast cancer cells and cell lines resulted in increased numbers of cells capable of repopulating tumors in NOD/SCID mice. Engraftment of cells with CSC like properties (side population) was inhibited by pretreatment with ErbB kinase inhibitors or by in vivo treatment with trastuzumab. An ErbB3 binding protein EBP1, cloned in our laboratory, appeared to decrease side population cells. They are interested in how manipulation of ErbB pathways may affect propagation of breast cancer stem cells.
Dr. Martin’s lab team has demonstrated that rare breast cancer cells with increased stem cell characteristics have greater ability than the predominant “bulk” cells in breast cancers to metastasize through novel microtentacles that they discovered. They are developing new therapies to target these microtentacle-containing breast cancer stem cells. They have also shown that some current chemotherapies increase the stem cell characteristics of breast cancers, raising the possibility that some existing cancer drugs which shrink the bulk of breast cancers may inadvertently increase the cancer stem cells which sustain the breast cancer. Through collaborations with engineers and physicists at the University of Maryland College Park, Johns Hopkins and a local Maryland company (Creatv MicroTech), they are developing devices to analyze live tumor cells from breast cancer patients. These techniques have revealed that microtentacles are detectable on patients’ cancer cells removed at surgery. The sensitivities of these putative cancer stem cells can be measured to help decide which drugs will most effectively treat the stem cells of individual patients and thus reduce metastases and recurrences.
Dr. Rapoport lab utilizes hematopoietic stem-progenitor cells clinically for bone marrow transplants and cell therapies. During an ongoing long-term collaboration with Dr. Carl June at the University of Pennsylvania, Dr. Rapoport has conducted 5 clinical trials (involving more than 150 patients) using adoptive T cell transfers in combination with tumor antigen immunizations to rebuild antimicrobial and antineoplastic immune function after autologous stem cell transplants for hematological malignancies. Current studies include a trial of adoptively transferred T cells genetically engineered to recognize myeloma-associated cancer-testis antigens including NY-ESO-1/LAGE-1.
The Rassool lab is interested in the DNA damage response (DDR) of embryonic stem cells in maintaining genomic integrity, and determining whether induced pluripotent cells (IPSCs) generated by different technologies produce a similar DDR. Her lab is focused on the mechanisms and regulation of repair of DNA double strand breaks (DSBs), the most lethal form of DNA damage for mammalian cells. Her recent work suggests that c-MYC plays a key role in regulating DSB repair and that IPSCs that have a c-MYC expression signature have a DDR similar to that of ESCs.
Dr. Scheibner has identified certain tumor suppressor microRNAs, such as miR-27a, in acute leukemias, and is studying the roles of these microRNAs in normal hematopoietic stem-progenitor cells. Dr. Scheibner is studying several other candidate tumor suppressor microRNAs thought to be involved in both acute leukemia and normal stem cell maintenance. In addition, an ongoing collaboration with Dr. Feyruz Rassool involves examining the role of microRNAs in double strand DNA break repair in normal hematopoietic stem cells and acute leukemias.