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.

Myelodysplasia and acute myeloid leukemia are blood cancers with a poor prognosis. At the root of these malignancies are cells harboring mutant forms of proteins with dysfunctional activity which results in abnormal cell behavior and drives disease progression. The focus of my project is the development of new therapeutics that precisely identify cells with mutant forms of the proteins and, by harnessing their aberrant biological activity, causes those cells to self-destruct. These selective therapeutics will be able to kill cancer cells but leave the healthy cells intact proving more effective and having less side-effects than the chemotherapies currently in use.

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.

About 70% of pediatric leukemias and 10% of adult leukemias are caused by a genetic disruption in which the mixed lineage leukemia (MLL) 1 gene breaks off and attaches to a different chromosome. This event, known as a chromosomal translocation, gives rise to a distinct subset of leukemias called MLL-rearranged acute myeloid and lymphoblastic leukemias (AML or ALL). Novel treatments for these cancers represent a major unmet medical need. However, the development of therapeutics is hampered by a lack of basic understanding of how the MLL translocations disrupt the function of affected cancer cells. Dr. Farnung will use biophysical and structural biology approaches to visualize how MLL translocations function at the atomic level and influence the important process of gene transcription. His work will elucidate the precise molecular mechanisms that drive acute leukemias and provide a platform for the development of novel therapeutic strategies against these cancers.

Many cancer diagnostic and treatment strategies use markers on the cell surface to find and kill cancer cells in a sea of healthy tissue. Dr. Flynn's research aims to expand our knowledge of what molecules are found on the surface of cancer cells. He will focus on acute myeloid leukemia (AML), as there is a major unmet clinical need for new curative treatments. Specifically, he aims to define RNA as a new cell surface molecule that could have unique structures on AML cells. With this knowledge he will develop antibodies to selectively detect cancer cells and enable tumor killing. Because tumors from other parts the body also express RNA on their surface, this strategy is expected to be broadly applicable to other cancer types.

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.