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Our group is interested in comparative analyses of normal lymphocyte development and malignant transformation towards leukemia. We cover research areas with relevance to Immunology, Hematology and Cancer Biology. Our research involves experiments with primary human leukemia cells, normal lymphocyte development in humanized mice, leukemia and stem cell transplantation models, mouse genetics, gene editing, genetic biosensors of signal transduction, optogenetics, classical molecular and cell biology, a strong emphasis on mechanistic studies in oncogenic signal transduction. We strive to promote a culture of diversity and inclusivity for all its members, focusing on career development and innovative approaches to science.

Qualifications:

Ph.D. in cell or molecular biology, enthusiasm for science, willingness to think beyond established concepts and to try and learn new experimental and analytical tools. The lab takes a team science approach, being collaborative is important as well.

Methods/Techniques:

Flow cytometry, mass spectrometry/quantitative phosphoprofiling, genetic biosensors of signal transduction, optogenetics, mouse genetics, bone marrow transplantation assays, retroviral gene delivery, whole-exome sequencing and RNA-seq-analysis of clonal evolution of leukemia, pre-clinical drug testing in xenotransplantation models.

Recent work of the laboratory:

To prevent the production of harmful autoantibodies and autoimmune disease, autoreactive B-cells and pre-malignant clones are eliminated by a process termed negative selection. Despite strict and rigorous negative selection, B-cells frequently give rise to autoimmune diseases and B-cell malignancies such as leukemia and lymphoma. Since humans can live without B-cells for extended periods of time, the Müschen laboratory systematically investigated lineage-specific vulnerabilities that are common in B-cell leukemia/lymphoma but not any other cell type. Contrary to the established dogma, these mechanisms are not only active in preventing autoimmune disease but also represent a novel class of therapeutic oncogenic targets in malignant B-cell tumors. Over the past five years, the Müschen Laboratory established innovative conceptual frameworks for the understanding of B-cell signaling mechanisms and negative selection, some of which are summarized below:

• We discovered regulation of energy-abundance as the central determinant of negative B-cell selection: Hyperactivation of kinases downstream of an autoreactive B-cell receptor induces ATP-depletion and energy stress (Chen Nature 2015, Shojaee Nature Med 2016, Chan Nature 2017; Pan PNAS 2020).

• Studying changes of energy metabolism during B-cell transformation, we discovered that glucose carbon-flux was diverted in a way that left transformed B-cells uniquely vulnerable to inhibition of PP2A, an enzyme that coordinates glycolytic flux with antioxidant protection (Xiao Cell 2018).

• We discovered that changes in cell size are orchestrated by BCL6 and MYC. Opposed by MYC, BCL6 decreases cell size by transcriptionally repressing glucose uptake in favor of autophagy (Duy Nature 2012; Geng Cancer Cell 2015; Hurtz Genes & Dev 2019).

• Tracking mechanisms of leukemia-initiation in 1,100 patients, we discovered pathway convergence as a novel therapeutic vulnerability in B-ALL. Only mutations that converged on one central pathway promoted leukemia progression. Genetic reactivation of divergent (suppressed) pathways engaged conflicting biochemical and transcriptional programs and subverted leukemia development. Pharmacological pathway reactivation to create a diverse signaling environment represents a novel strategy to prevent B-ALL relapse and drug resistance (Chan Nature 2020).

• Studying biophysical mechanisms of B-cell activation, we discovered that the short endosomal protein IFITM3 acts as a central scaffold for lipid-raft assembly and surface-expression of rafts-associated receptors. Membrane-recruitment of IFITM3 was essential for the initiation of PI3K-signaling, antibody affinity maturation and oncogenic B-cell transformation (Lee Nature 2020).

Your application should include in one single PDF:

CV, a brief statement of motivation, and contacts of three scientific mentors (references) sent to Dr. Markus Müschen via email.

Job Description:

?We are seeking a highly motivated postgraduate research associate interested in joining the Müschen Lab to gain experience in the fields of cancer genomics, systems biology, and bioinformatics. You will have the opportunity to work with a team of scientists dedicated to studies on B-cell development and targeted cancer therapy. Our research involves experiments with leukemia cells, mouse models, and we largely employ molecular and cellular biology tools to understand the mechanisms driving malignant transformation through signaling pathways. Under the guidance of Dr. Markus Müschen and senior lab members, you will also have the opportunity to contribute to the ongoing research projects and take part in high-impact publications. This is a full-time position available for 1-year with the possibility of renewal.

Over the past 12 years, our laboratory has developed a multidisciplinary research program focused on oncogenic signaling and clonal evolution in B-cells. Antibody-producing B-cells are under intense selective pressure to remove autoreactive and pre-malignant clones, yet autoimmune disorders and B-cell malignancies such as leukemia are very common and often incurable diseases. By understanding the mechanisms of B-cell selection, we are able to explore new therapeutic targets in B-cell tumors. Our scientific discoveries are driven by the desire to create a stimulating academic environment where we focus on rigorous, collaborative, and innovative science.

You will work closely with our senior scientists to help advance their innovative research projects focused on B-cell development, mechanisms of negative selection and approaches to therapeutic targets in B-cell malignancies. We rely heavily on molecular and cellular approaches, so you must be enthusiastic and willing to learn about new techniques and technologies in the field of genomics, proteomics, transcriptomics to tackle your work. This training will promote your understanding of cancer biology and you will be able to contribute to exciting research projects in a multidisciplinary setting. Prior experience handling experimental mice (injection, genotyping, colony maintenance) is a plus given that we use genetic mouse models to address normal and malignant hematopoiesis. You will be expected to actively participate in our weekly lab meetings, provide work-in-progress updates, and take part in our scientific club discussions. You will also work closely with our lab manager and assist him with the general upkeep of the lab and organizing our inventory.

In the laboratory, we promote a culture of inclusivity, mentoring our trainees’ scientific growth, and striving to make science accessible to everyone. Through daily interactions with senior lab members and weekly sessions with Dr. Müschen, you will have the support necessary to develop into a successful independent scientist if that is your goal. You will be given advice on career development and will have the opportunity to conduct your own project(s).

Requirements:

Bachelor’s or Master’s degree in biological sciences or related field with practical experience in basic molecular and cell biology techniques (e.g., cell culture, protein chemistry, western blotting, quantitative PCR, cloning, etc). Basic knowledge of cancer genomics, immunology or hematology is a plus.

Your application should include in one single PDF:

CV, a brief statement of motivation, and contacts of three scientific mentors (references) sent to Dr. Markus Müschen via email.

We are currently seeking a highly motivated postgraduate associate with experience in bioinformatics to join the Müschen Lab in the Center of Molecular and Cellular Oncology at the Yale Cancer Center. Our multidisciplinary team bridges clinical, genetic and computational approaches to understanding mechanisms of oncogenic signaling and B-cell selection, allowing us to explore novel therapeutic strategies in B-cell malignancies including B-ALL, CLL and MCL. Our scientific discoveries are driven by the desire to create a stimulating academic environment where we focus on rigorous, collaborative and innovative science.

You will work closely with our bioinformatics teams to hone your computational skills and collaborate with bench scientists to explore biological questions. Career development and project guidance will be provided by frequent discussions with Dr. Müschen. The assignments will focus on high-throughput data analysis and interpretation - from raw data sequence processing through to biological insights and visualization and for presentation and publication. Techniques include proteomics, phosphoproteomics, ChIP-seq, transcriptomics, single-cell BCR- and RNA-sequencing and genomics. This includes both analyses of public datasets for identification of B-cell specific vulnerabilities and internally generated datasets to answer hypothesis-driven questions. This is a great opportunity to develop command-line scripting, high-performance computing environments, R- and python programming, and data visualization. In addition to technical training, you will gain an in-depth understanding of molecular oncology, specifically in B-cell malignancies. Prior experience or familiarity with analysis pipelines, algorithms, or experimental protocols for any of the above techniques would be considered a plus.

In the laboratory, we promote a culture of inclusivity, mentoring our trainees’ scientific growth, and striving to make science accessible to everyone. It’s our aim that through daily guidance from our lead bioinformatician and weekly sessions with Dr. Müschen you will have the support necessary to develop into a successful independent scientist. You will also have the opportunity to attend conferences and courses on programming, bioinformatics, machine learning and oncology. Participation in Yale’s mentorship program is also strongly encouraged.

A Bachelor’s or Master’s degree in any biological, computational or other quantitative science is required for this position. A track record of experience in bioinformatics - either coursework or practical experience is preferred. To excel in this role you must have a passion for exploring challenging research questions in an interdisciplinary team setting, be organized, motivated and have excellent communication and problem-solving skills. Experience in the fields of cancer genomics or hematology is preferred but not required.

Your application should include in one single PDF:

CV, a brief statement of motivation, and contacts of three scientific mentors (references), sent to Dr. Markus Müschen via email.