Over the past 10 years, the Müschen laboratory has developed a multidisciplinary research program to study oncogenic signaling and clonal evolution in acute lymphoblastic leukemia (ALL), the most frequent type of cancer in children and young adults. Despite increasing survival rates over the past decades, around 70 percent of children who relapse still die from their disease. With current algorithms of risk stratification, relapsing patients are undistinguishable from patients who will respond well to standard chemotherapy. Many of the approximately 110,000 survivors in the U.S. who would benefit from milder forms of chemotherapy are nonetheless treated with aggressive regimen and suffer late effects from unnecessary toxicity.
For these reasons, Müschen’s group has developed a comprehensive research program to predict relapse of ALL. Applying forward genetic screens in PDX models, his drug-discovery program will leverage newly discovered vulnerabilities to broaden treatment options and validate a diagnostic test. Müschen’s research is guided through close collaboration with clinician-scientists in the Children’s Oncology Group, a clinical trials group supported by the National Cancer Institute. As principal investigator of the National Cancer Institute’s Cancer Therapy Evaluation Program “preclinical drug-testing” project, he developed a testing platform with clinical, phenotypic and genetic annotation.
After medical training in Germany and France, Müschen completed his M.D. thesis in biochemistry (summa cum laude) in the laboratory of Helmut Sies and joined the laboratories of Ralf Küppers and Klaus Rajewsky in Cologne and Janet D. Rowley in Chicago for postdoctoral training. In 2006, he was recruited to the U.S. to start his independent laboratory at the University of Southern California and Children’s Hospital Los Angeles.
In 2010, Müschen joined the faculty of the University of California San Francisco (UCSF) and was promoted to full professor and program leader of the Hematological Malignancies Program at the UCSF Comprehensive Cancer Center. In 2017, he joined City of Hope as The Norman and Sadie Lee Foundation Professorship in Pediatrics and as chair of the Department of Systems Biology. Given his main research interest in diagnosis and prevention of childhood ALL relapse, Müschen was also appointed associate director of pediatric oncology of City of Hope's National Cancer Institute-designated comprehensive cancer center.
Müschen has been named a scholar of the Leukemia & Lymphoma Society, a senior investigator of the Wellcome Trust at the University of Cambridge (U.K.), and Sir Alexander Haddow Professor of the Institute for Cancer Research in London. He is currently a Howard Hughes Medical Institute Faculty Scholar. In 2015, at age 42, he was selected as the youngest recipient in inaugural class of the National Cancer Institute ‘Outstanding Investigator Awards’ (R35).
Ali obtained his Ph.D. from Erasmus Medical Center in Rotterdam, The Netherlands and his work in Professor Frank Grosveld’s laboratory mainly focused on ƴ-globin reactivation during human hematopoiesis. He subsequently joined the BLUEPRINT project (mapping human blood cell epigenomes) in Professor Henk Stunnenberg‘s laboratory in Nijmegen, The Netherlands. Ali Aghajanirefah then joined the Müschen laboratory at the University of California, San Francisco (UCSF) in 2015 and moved with the group to the Beckman Research Institute in May 2017. Ali Aghajanirefah is mainly interested in BTB-domain transcriptional repressors, including BCL6, BACH2 and BCOR. For detailed biochemical studies, Ali developed genetic systems for inducible deletion of Bcl6, Bach2 and Bcor in B-lymphoid and myeloid lineages as well as various leukemia subtypes.
Franziska Auer completed her graduate training in molecular biotechnology at the Technical University Munich (TUM), before she moved to Duesseldorf for her Ph.D. at the Heinrich-Heine University (HHU) Düsseldorf. Dr. Auer’s Ph.D. thesis titled "Paired Box 5 (PAX5) in B cell precursor acute lymphoblastic leukemia," was performed in Professor Arndt Borkhardt’s laboratory in the Department of Pediatric Oncology, Hematology and Clinical Immunology of the Düsseldorf University Medical Center. Franziska Auer also trained with Dr. Isidro Sánchez-García and worked in his laboratory in Salamanca, Spain.
In May 2017, Dr. Auer joined the Müschen laboratory in the Department of Systems Biology as a Postdoctoral Fellow. Her project involves the study of negative feedback regulations in pre B-cell Receptor (pre-BCR) signaling in precursor B-cell acute lymphoblastic leukemias (pre-B ALLs). Her other research interests include pediatric leukemias, B-cell specific transcription factors and pre-BCR signaling.
Kadriye Nehir Cosgun
Kadriye Nehir Cosgun is a postdoctoral fellow and mainly interested in the basic mechanisms of hematopoiesis and leukemic transformation. One of her projects focuses on the role of pre-B cell signaling in acute lymphoblastic leukemia. In 2008, Dr. Cosgun completed her graduate training in molecular biology degree with high honors at Bilkent University in Turkey. She was subsequently admitted to the Dresden International Ph.D. program in Dresden, Germany. Her Ph.D. thesis, titled “Kit regulates HSC engraftment across mouse human species barrier” was supervised by Professor Claudia Waskow and awarded the “The best Ph.D. thesis in 2013” by the Center for Regenerative Therapies Dresden. In 2014, Nehir joined the Müschen laboratory at the University of California, San Francisco and moved with the group to the Department of Systems Biology of the Beckman Research Institute of City of Hope in May 2017. Her current work focuses on the role of Lgr5 and WNT signaling in B cell selection and the malignant transformation of B cells.
Lars Klemm joined the Müschen Laboratory in 2005 and acquired his master's of science (M.sci.) degree in molecular and cell biology from the Heinrich-Heine-University Düsseldorf, Germany in 2009. His work focused on the activation-induced cytidine deaminase (AID) and how it promotes genetic instability in B-lymphoid malignancies (Klemm et al., Cancer Cell 2009, Swaminathan et al., Nature Immunol 2015). Lars Klemm moved with the Müschen Laboratory from Düsseldorf, Germany in 2006 and has been the lab manager of the research group. Lars Klemm joined the Department of Systems Biology of the Beckman Research Institute as technology manager of the department, overseeing laboratory operations and design and the set-up of all major technical equipment and research infrastructure of the research groups.
Kohei Kume obtained his Ph.D. from the United Graduate School of Agricultural Sciences, Iwate University (UGAS), Japan in 2011 and completed a postdoctoral fellowship at Iwate Medical University in 2015, working with Professor Satoshi Nishizuka. After joining the Institute of Biomedical Science at Iwate Medical University as an instructor, he joined Markus Müschen’s laboratory as a postdoctoral fellow in the Department of Systems Biology at Beckman Research Institute in 2017. Kohei Kume studies the mechanisms of autonomous calcium oscillations in oncogenic signaling of B-lymphoid leukemia cells and the functional significance of these calcium oscillations. His work includes genetic studies of Orai and Stim1 Ca2+
channels as well as imaging systems to track Ca2+ flux as part of oncogenic signaling in live cells.
Theano Panagopoulou acquired an integrative master’s of science (M.Sci.) degree in molecular and cell biology from the University of Glasgow in 2013. As part of her integrative degree program, she joined the University of Tampere, where she conducted research under the supervision of Professor Tapio Visakorpi. Shortly after graduating from the University of Glasgow she joined the University of Edinburgh in order to complete her Ph.D. at the Scottish Center for Regenerative Medicine, under the supervision of Professor Kamil R. Kranc. During her PhD she focused on the role of the metabolic enzyme fumarate hydratase in aged hematopoiesis and in malignant transformation. After she successfully defended her thesis, Dr. Panagopoulou joined Markus Müschen’s laboratory as a postdoctoral fellow, in the Department of Systems Biology of the Beckman Research Institute of City of Hope. Her current project focuses on comparative analyses of matched sample pairs from patients with B cell lineage ALL at the time of diagnosis and subsequent relapse.
Teresa was awarded her Ph.D. in genetics from the University of Adelaide, South Australia, in 2014 for her thesis entitled “Investigation of the role and mechanism of β-catenin activation in acute myeloid leukemia”. She then joined the Leukemia Laboratory of Professor Tim Hughes and Deborah White at SAHMRI as a postdoctoral fellow, where she was part of the Australian Genomics Healthcare Alliance for three years. In this time she gained expertise and a strong interest in Acute Lymphoblastic Leukemia (ALL) genetics and personalized medicine, particularly in the establishment of platforms for the rapid identification of targetable lesions in patients with ALL. Teresa joined the Müschen Laboratory in January 2017 where she hopes to further pursue her research goals of understanding the genetics and signaling networks driving leukemogenesis. Her current project is focused on understanding the role of Syk-family kinases in B-cell malignancies.
Hongbin Wang received his Ph.D. degree from Institut Pasteur of Shanghai under the supervision of Professor Guangxun Meng in 2015. His Ph.D. study focused on mechanisms of the NLRP3 inflammasome activation during innate immune response. Hongbin Wang then continued his studies of the inflammasome’s roles in virus infections and antiviral drug development in the Meng laboratory as a postdoctoral fellow. In July 2017, he joined the Müschen laboratory to deepen his interest in lymphocyte signaling and leukemia and lymphoma biology His current research project focuses on chronic active BCR signaling in mantle cell lymphoma (MCL) and genetic events leading to gradual transformation of early B cell precursors.
Chengsheng Wu received his Ph.D. degree from the University of Alberta, Canada in January 2017. In his Ph.D. study, he worked on the molecular mechanisms underlying the pathobiology of ALK-positive anaplastic large cell lymphoma (ALCL), with a focus on the JAK/STATs signaling and the Wnt/β-catenin pathway in ALCL. In February 2017, Wu joined this lab as a post-doc fellow. Currently, he is working on a project about the potential biological significance of MUC4, a highly glycosylated protein usually found in epithelial cells, in precursor B cell acute lymphoblastic leukemia (pre-B ALL). While high expression levels of MUC4 are predictive of poor clinical outcome in pre-B ALL, its expression levels are particularly high in Ph+ and Ph-like ALL.In epithelial cancers, MUC4 can associate with the ERBB2 receptor tyrosine kinase (RTK). In Ph+ ALL, the BCR-ABL1 kinase can phosphorylate the C-terminus of MUC4 and we hypothesize that it amplifies oncogenic BCR-ABL1 kinase signaling similar to its interaction with RTKs in epithelial cancers.