Dr. Matthew Witkowski: 2020 CDP Achievement Award Winner

Dr. Witkowski

2020 LLS-CDP FELLOW ACHIEVEMENT AWARD

Dr. Matthew Witkowski was awarded his PhD degree at the Walter and Eliza Hall Institute in Melbourne, Australia based on his studies in the laboratory of Dr. Ross Dickins. He received the LLS CDP Fellow award while doing a postdoctoral fellowship at New York University School of Medicine in the laboratory of Dr. Iannis Aifantis establishing himself in a new field: the dissection of the targetable components of the leukemic immune microenvironment amenable to novel therapeutic intervention. His strong commitment to understanding acute lymphoblastic leukemia (ALL) biology and extensive postdoctoral training in understanding the normal and leukemic microenvironment provides him with a skillset that ideally positions him to address these timely topics. His career trajectory in outstanding research laboratories across countries highlights his focus and passion for pursuing his independent professional goals. Dr. Witkowski is currently Assistant Professor at University of Colorado – Anschutz Medical Campus expanding his research on leukemia microenvironment.

While it is extremely difficult to accurately quantify the many benefits of a postdoctoral fellowship, I will provide the best summation of how important the LLS Career Development Program (CDP) Fellowship was to my own career and personal development. In 2015, I left Melbourne, Australia to join Iannis Aifantis’ laboratory at New York University Langone Health as a postdoctoral researcher studying the microenvironment of acute leukemia. The early stages of my postdoctoral research were met with a constant feeling of “imposter syndrome” as I painstakingly inched toward my scientific goals. Along with the immense support of the Aifantis laboratory, receiving the LLS CDP award really helped steady the ship. This recognition of my scientific ideas, efforts and potential boosted my confidence as a young researcher and helped propel me toward my goal of becoming a leader in field of pediatric leukemia biology. As I prepare for my research independence, I cannot thank the LLS enough for their generous investment in both my scientific pursuits and personal development. This outstanding program continues to elevate young researchers and I feel honored to have been named an LLS CDP Fellow.

 

Dr. Witkowski was awarded the CDP Fellow Award in 2016 for his project titled Understanding the function of 3D chromatin topology in myeloid disease.

Greater understanding of the fundamental mechanisms promoting the development of acute myeloid leukemia (AML) may help researchers develop new treatment approaches targeting these mechanisms. Chromosomes are heritable and dynamic carriers of genetic information. Chromosomes are constantly looping, and these structural changes shape the gene expression pattern of a cell. This 3D genome landscape, known as genome topology, provides the physical structure required to inform the identity and function of a cell. The key players in establishing genome topology include the cohesin complex, a group of proteins that physically wraps around DNA to establish looping events, as well as the CTCF protein, which acts to bind DNA and establish the boundary of genome topological domains. Though genomic topological changes are normal in a healthy cell, alterations in genome topology likely play a role in cancer development. Interestingly, regulators of genome topology are commonly mutated in various diseases, including cancers such as AML. AML is a common adult leukemia characterized by excessive proliferation of abnormal immature white blood cells. AML patients continue to have a dismal survival rate. Notably, mutations in the cohesin complex are an early step in AML formation, suggesting that controlling DNA looping and overall genome topology is a critical function to prevent cancer. However, there are limited insights into how maintaining the topological integrity of the genome halts AML formation. Our research focuses on understanding how regulators of the genome’s 3D structure protect healthy blood stem cells from forming leukemia. Using cutting edge technology, such as inducible RNA interference and CRISPR/Cas9, we will shed new light into the earliest steps in leukemia formation. Ultimately, mechanistic insights uncovered by these approaches have the potential to inform new treatment strategies targeting the root genetic causes of leukemia development.

During the award period (2017-2020) Dr. Witkowski focused to build on his extensive commitment to understanding blood malignancies, particularly on high-risk pediatric ALL and dissecting the primary human B-ALL bone marrow immune microenvironment throughout chemotherapy. Some highlights:

  • utilized novel single-cell profiling techniques to map the B-ALL patient bone marrow immune cell microenvironment throughout three distinct stages of the leukemic disease process: diagnosis, remission and relapse
  • identified a novel role for leukemia-associated nonclassical monocytes in promoting B-ALL survival
  • showed that pharmacological targeting of the tumor-associated monocytes subpopulations using M-CSFR inhibiting monoclonal antibody enhanced the responsiveness to existing therapy

All first author publications during the award period:

  • Cancer Cell. 2020 Jun 8;37(6):867-882.e12.
  • Trends Cancer. 2019 Oct;5(10):604-618.
  • J Exp Med 217 (2): e20190589