Patients with relapsed blood cancers after allogeneic stem cell transplant are often treated with donor lymphocyte infusion (DLI), a type of immunotherapy that boosts the anti-tumor response and aims to induce cancer remission. The success of DLI varies from patient to patient. Dr. Bachireddy aims to investigate the determinants of DLI success and failure by studying the leukemic and immune cells during response to immunotherapy. Careful study of successful anti-tumor immune responses may reveal insights into tumor-immune interactions that may be relevant to predicting patient response to novel immunotherapies in other tumors.

Myeloid neoplasms (MN), including acute myeloid leukemia and myelodysplastic syndrome, are lethal blood cancers. The genetic mutations in the blood that lead to MN can occur years before diagnosis and maintain almost normal function before transformation. Certain mutations, including those in the gene IDH2, have been identified as high-risk for developing MN. Individuals with a reduction in the number of mature blood cells (cytopenias) who harbor acquired mutations in their blood, yet do not meet criteria for a cancer diagnosis, have a condition called cytopenias of undetermined significance (CCUS). These individuals almost invariably develop MN. Dr. Bolton will conduct a clinical trial to evaluate whether the IDH2 inhibitor enasidenib can be used as a therapy for CCUS. She will assess mechanisms of resistance and determine whether enasidenib can prevent the development of MN. This represents the first use of genetically targeted therapy for cancer prevention.

Acute myeloid leukemia (AML) is an aggressive blood cancer that affects children and adults. One particularly difficult-to-treat subtype of AML that represents about 10% of all cases is characterized by a mutation in the KMT2A gene. Menin inhibitors (MI), a novel targeted therapy, have shown promise against this subtype in early clinical trials. Studies have also shown that compounds that degrade a protein called Ikaros can dramatically enhance the efficacy of MI. In seeking to uncover why MI and Ikaros protein degraders work well together, Dr. Bourgeois and his colleagues have found that both drugs target gene expression programs that are critical for the survival of KMT2A-mutant AML cells. Dr. Bourgeois is now working to better understand which genes can be targeted to further enhance the efficacy of Ikaros protein degraders in KMT2A-mutant AML. This work will shed light on the essential gene expression programs required for KMT2A-mutant AML cell survival, and ideally help guide drug development that specifically targets this subtype.

Dr. Crosse [Illini 4000 Fellow] focuses on myelodysplastic syndromes (MDS), blood cancers that occur predominantly in the elderly. These cancers are initiated in the bone marrow when blood stem cells acquire a genetic mutation that causes them to divide and multiply uncontrollably. Through proliferation and acquisition of further mutations, the disease can evolve into acute myeloid leukemia, for which prognosis and survival rate are typically poor. Dr. Crosse aims to identify the specific blood stem cells that are most impacted by the mutation in the early stages of MDS and determine how they contribute to disease progression. The goal is to design therapies that inhibit these mechanisms and halt MDS cancer progression.

Kaposi's sarcoma herpesvirus (KSHV) is a human oncogenic virus and the causative agent of cancers including Kaposi’s sarcoma, primary effusion lymphoma, and Multicentric Castleman disease. The related human herpesvirus Epstein-Barr Virus (EBV) is even more prevalent than KSHV, and is linked to cancers including Burkitt’s lymphoma, Hodgkin’s lymphoma, and nasopharyngeal carcinoma. Dr. Didychuk [The Rhee Family Breakthrough Scientist] is investigating the mechanisms by which KSHV co-opts the cellular host machinery to produce its own gene products in a manner distinct from other viruses and host cells. A molecular understanding of how herpesviruses hijack the late gene transcription machinery will reveal new therapeutic weaknesses in the viral lifecycle and allow for structure-guided design of novel anti-viral drug targets.

Mutations in the cancer-causing oncogene JAK2 are a hallmark of myeloproliferative neoplasms (MPNs), a blood disorder characterized by over-production of mature blood cells. While currently available JAK2 inhibitors improve symptoms, they are unsuccessful at completely eradicating diseased cells, so remissions are rare. Using genetically engineered mice, Dr. Dunbar will investigate how MPN cells remain dependent on JAK2 signaling for cell growth, and how additional mutations in the epigenome (the proteins involved in regulating gene expression) might contribute to drug resistance. His research aims to identify improved JAK2 inhibitors and lend insight into whether targeting both oncogenic drivers and epigenetic defects could be required for effective therapy. Ultimately, he hopes these findings will translate into better treatments for patients with these cancers.

Dr. Eisen [David Ryland Fellow] studies how a class of enzymes known as the Tec kinases help to activate the immune response. Two of these kinases, Itk and Btk, are remarkably similar in sequence composition and structure but play distinct roles in immune cells. Dr. Eisen is using high-throughput methods to understand the differences between these enzymes. This work will also aid in the overall molecular understanding of Btk, which is a therapeutic target of B-cell lymphoma and is inhibited by the chemotherapeutic ibrutinib.

Blood stem cells, which give rise to various blood cells in the body, acquire mutations with increasing frequency as we age. In the absence of blood cancer development, this state is called clonal hematopoiesis. Up to a quarter of individuals over 60 years old will have recurrent mutations detected in their blood. Recent studies suggest that those with clonal hematopoiesis have an increased risk of developing heart disease and blood cancer, as well as increased levels of inflammatory cytokines – signaling molecules released by immune cells to promote inflammation. Dr. Kim will dissect the mechanisms underlying increased inflammation, which could provide insight into various inflammatory conditions associated with clonal hematopoiesis and potentially elucidate how clonal hematopoiesis progresses into blood cancer.

Cancer cells harboring many genetic changes in their DNA often express novel proteins called neoantigens that activate the immune system to recognize and attack the tumor. Based on this mechanism, researchers are developing novel treatments to stimulate the immune system's response against a tumor, but this approach may not work for pediatric cancers that carry few genetic mutations. Dr. Knoechel's research is investigating alternative ways neoantigens can be generated, such as splicing or epigenetic changes, which occur frequently in leukemia and pediatric cancers. She is focusing on T-cell acute lymphoblastic leukemia (T-ALL), an aggressive blood malignancy in children and young adults that frequently stops responding to treatment causing relapse. Her research aims to identify mechanisms of immune "exhaustion" when T-cells stop fighting a tumor, define neoantigens generated by non-genetic mechanisms, and develop novel strategies to target non-genetic neoantigen expression. This research may lead to novel immunotherapy strategies for pediatric tumors.

Dr. Kory studies the role of mitochondria in metabolic homeostasis and signaling, with a focus on mitochondrial transporters. Mitochondria are critical organelles in metabolic functions, generating the energy and compounds needed to construct the building blocks of the cell.   However, they have been hard to identify and even harder to study mechanistically. She will approach the problem using innovative functional genomics and metabolomics tools. As cancer cells rely on an increased supply of energy to fuel their rapid proliferation and ensure survival in the harsh tumor microenvironment, these studies aim to lay the groundwork for future development of metabolic inhibitors with potential chemotherapeutic value.