Uterine Serous Carcinoma
Uterine cancer is the 4th most common cancer in women and its incidence is increasing. Regrettably, the survival rate for uterine cancer has been stagnant since the mid-1970s, and mortality rates have increased by 2% each year for the past decade. Worsening outcomes are primarily due to a rise in the incidence of high-risk uterine cancer subtypes, especially uterine serous carcinoma (USC). Whereas the yearly incidence of low-grade uterine cancers was stable between 2001 and 2017, the incidence of USC increased by 4.9% annually. USC arises in post-menopausal women, is highly aggressive, and carries a dismal 5-year cancer related survival of 50%. Although USC constitutes only 10% of total uterine cancer cases, it is responsible for 40% of uterine cancer deaths. USCs invade and metastasize rapidly, and 40% of USC patients have metastatic disease at diagnosis due to spread through the uterine lymphatics or direct extension into the pelvic cavity. In contrast, 50% of USC patients have non-metastatic disease that is limited to the uterine body at diagnosis, a finding that corresponds to International Federation of Gynecology and Obstetrics (FIGO) stage I disease. These patients should be cured by staging hysterectomy. However, USC will ultimately recur in 30% of these patients, an event which is associated with poor outcomes. Contemporary molecular, surgical, histologic, and imaging modalities cannot predict which patients with FIGO stage I USC will recur after surgery. For this reason, the National Comprehensive Cancer Network (NCCN) guidelines recommend that physicians consider adjuvant chemotherapy +/- radiation in virtually all FIGO stage I USC patients. Our laboratory has identified GATA Binding Protein 2 (GATA2) as a transcription factor that regulates USC invasion and metastasis, and we find that it predicts USC recurrence after staging hysterectomy. In tandem with clinical trials evaluating the effectiveness of GATA2-guided personalized therapy for USC patients, our laboratory is investigating the molecular mechanisms through which GATA2 regulates USC behavior.
Benign and Malignant Hematology
Germline mutations in GATA2 lead to the GATA2 Deficiency Syndrome, which predisposes to bone marrow failure and acute myeloid leukemia via unknown mechanisms. Sporadic GATA2 mutations can also be found in cases of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) where their significance is unknown. GATA2 RNA transcripts are elevated in MDS and AML and GATA2 is hypothesized to form a positive feedback loop with p38 in AML cells which promotes AML proliferation. In acute promyelocytic leukemia (a subtype of AML), GATA2 has been proposed to behave as a tumor suppressor by suppressing PML-RARA-driven cell growth. GATA2 is also a critical regulator of benign hematopoietic stem cells and it is believed to maintain this function in leukemic stem cells. GATA2 RNA transcripts may also be elevated in a subset of pediatric B-acute lymphoblastic leukemias where the significance of this finding is unclear. Finally, GATA2 is predicted to be specific for the myeloid lineage by RNA expression studies. Critically, GATA2 protein levels have never been measured in MDS or acute leukemia. We generated anti-GATA2 monoclonal antibodies which can readily detect mouse and human GATA2 in diverse assays. With the addition of new tools in development, we are working to identify critical GATA2 mechanisms regulating healthy and malignant hematopoiesis.