This project aims to better understand the biology of acute myeloid leukemia (AML), a blood cancer that affects white blood cells. The most common form of AML in adults involves a specific mutation in a gene known as NPM1. This mutation occurs in a consistent way and drives the growth of leukemia cells. Dr. Liu is investigating how this NPM1 mutation alters the behavior of leukemia cells and response to drug treatments, with the goal of developing new and more effective treatments for patients with this disease.

Although hematopoietic stem cell transplantation is the only curative treatment for some pediatric leukemia patients, chronic graft-versus-host disease (cGVHD) is a potentially life-threatening immune complication of stem cell transplantation. Li’s research aims to mitigate the effects of cGVHD by enhancing the activity of regulatory T cells (Tregs), which are immunosuppressive T lymphocytes. Specifically, she is studying the effect of a novel class of drugs called thalidomide analogs on Treg survival and function. Li will use genetic screens, cell culture and mouse models to elucidate the mechanisms by which thalidomide analogs alter Treg activity and to determine whether treatment with thalidomide analogs can mitigate cGVHD severity. She hopes that these studies will identify methods to strengthen Treg function and inform novel strategies to improve therapies for cGVHD. Li received her PhD from the Massachusetts Institute of Technology, her MD from Harvard Medical School, Boston, and her BA from Harvard University, Cambridge. 

Acute myeloid leukemia (AML) is a type of blood cancer that affects children and is treated with intense chemotherapy. Unfortunately, if this cancer recurs, it is difficult to treat with chemotherapy. More than half of children with recurrent AML die from the disease. Patients with recurrent AML are typically treated with immunotherapy, a type of treatment that leverages the body’s immune system to kill cancer. Phillips studies a type of natural killer cell called memory-like natural killer cells, which have an enhanced ability to kill AML. Her project aims to help memory-like natural killer cells better recognize AML cells by outfitting them with one of two receptors, chimeric antigen receptors or natural killer cell engagers, to target common markers on the surface of AML cells. She hopes one or both methods can be translated into a clinical trial to treat children with chemotherapy-resistant AML. Phillips received her MD from the Medical College of Wisconsin and her BS from the University of Wisconsin-Madison. 

Dr. Chan’s [Sijbrandij Foundation Fellow] research focuses on gamma delta T cells, an unusual and understudied population of immune cells. While gamma delta T cells have strong antitumor activity, they are most highly stimulated not by cancer cells but by signals produced by microorganisms. Dr. Chan’s work examines the mechanisms by which gamma delta T cells detect and respond to leukemia versus pathogenic microorganisms, and how infection with these microorganisms subsequently impacts the trajectory of leukemia. This is particularly relevant to patients undergoing conventional cancer treatments (e.g., chemotherapy) that suppress the immune system, rendering them susceptible to infection. Furthermore, gamma delta T cells are capable of both rapid and long-term responses against their targets, which positions them as a tool to treat initial cancer as well as prevent disease recurrence. Dr. Chan received her PhD from Yale University, New Haven, and her BS from the University of California, Los Angeles.

Acute myeloid leukemia (AML) is an aggressive blood cancer, diagnosed in about 20,000 people in the U.S. each year. New targeted therapies have greatly expanded treatment options, particularly for older adults who cannot tolerate chemotherapy, but despite these advances, most patients with AML will experience relapse. Research has identified that mutations in the RAS signaling pathway are associated with relapse after targeted therapies. Dr. Anandappa aims to establish a role for RAS inhibitors in treating AML and elucidate the role of inflammation in RAS-mutated AML. She will use CRISPR to study over 300 genes involved in inflammatory signaling and determine if blocking them will increase response to treatment with a RAS inhibitor. The outcomes of this project will ultimately guide the design of combination regimens for the treatment of RAS-mutated AML.

Dr. Gu’s [Sijbrandij Foundation Breakthrough Scientist] lab studies how cells regulate the destruction of proteins without using the typical "ubiquitin" tag, which signals that a protein should be transported to the proteasome for digestion and recycling of amino acids. The lab has discovered a new pathway, the midnolin-proteasome pathway, that helps degrade key proteins involved in cancer, including several linked to blood cancers like multiple myeloma. The lab’s goal is to understand this pathway better and explore how it might be used to develop new treatments, especially for blood cancers, by targeting specific proteins that drive disease.

Hematopoietic stem cells, which are found in the bone marrow and give rise to all other blood cells, maintain lifelong blood production and immune function. Due to their remarkable ability to regenerate the entire blood system, medical uses of HSCs have provided cures for many previously incurable diseases, including blood cancers. However, several unanswered questions limit our ability to full harness their therapeutic potential for cancer treatment. What regulates HSC regeneration? Why does their function decline with age? How does HSC behavior vary in healthy individuals? Using cutting-edge single-cell analyses and computational biology, Dr. Gao [HHMI Fellow] aims to identify the molecular and cellular factors involved in HSC regeneration, as well as possible targets for enhancing their regenerative potential. This work could enable significant improvements in stem cell-based therapies for cancer treatment. Dr. Gao received his PhD from Harvard University, Cambridge and his BS from Washington University, St. Louis.

The cellular response to DNA damage is coordinated by an enzyme known as ATM kinase. Mutations in ATM are found in approximately 1% of the population and contribute to an increased risk of both hereditary and sporadic cancers, including breast cancer. Dr. Kim’s [Lallage Feazel Wall Fellow] research investigates how ATM suppresses the production of double-stranded RNAs (dsRNAs) in response to DNA damage. These dsRNAs play a critical role in tumor progression. Dr. Kim aims to identify the key molecular players involved in ATM-mediated suppression of dsRNAs and elucidate how the loss of ATM function triggers inflammatory responses through dsRNA sensing pathways. By uncovering these mechanisms, Dr. Kim aims to deepen our understanding of how ATM mutations drive cancer development and uncover novel therapeutic strategies for ATM-associated cancers. Dr. Kim received his PhD and BS from the Ulsan National Institute of Science and Technology, Ulsan.

Drug therapies that selectively target proteins that drive the growth of tumor cells are rapidly becoming the standard of care for many cancers. However, tumors are often able to evade inhibition by targeted anti-cancer drugs by activating other proteins, leading to drug resistance. Dr. Gier [HHMI Fellow] is developing a new therapeutic approach that repurposes existing drugs to release highly toxic cargoes, known as payloads, that aggregate in drug-resistant cancer cells and kill them. As a general platform, it is applicable to a wide range of solid and liquid cancers. Dr. Gier received his PhD from University of Pennsylvania, Philadelphia and his BA from Swarthmore College, Swarthmore. 

Dr. Zhang is studying a unique three-stranded nucleic acid structure, called an R-loop, to understand its role in cancer development and find ways to target and control its formation. R-loops consist of a DNA-RNA hybrid and a displaced strand of DNA. R-loops occur frequently in human genomes, and while they play an important role in blood cell differentiation and immune cell function, they can also interfere with DNA repair and promote genome instability, giving rise to leukemia. However, the dynamic nature of R-loop formation hampers the detection of this structure in a small cell sample. To address this challenge, Dr. Zhang is developing novel techniques to map R-loops in normal blood stem cells versus blood cancer cells at single-cell resolution. He also plans to investigate leukemia-specific R-loops in vitro and in vivo with CRISPR-based screening techniques. The goal of his research is to aid development of therapeutic interventions for R-loop-related gene expression dysregulation in cancer, especially leukemia. Dr. Zhang received his PhD from Ohio State University, Columbus, his MS from University of Edinburgh, Edinburgh, and his BS from Chongqing University, Chongqing.