1018 - CD97 IS A CRITICAL REGULATOR OF ACUTE MYELOID LEUKEMIA STEM CELL FUNCTION

Despite advances in our understanding of the genetic origins of acute myeloid leukemia (AML), treatment options have remained essentially unchanged for 30 years, and clinical outcomes remain poor. AML is maintained by leukemia stem cells (LSCs), which are critical for disease maintenance as well as re-initiating disease after therapy. We previously identified novel markers and therapeutic targets in AML and MDS by comparing the transcriptomes of stem cells to normal purified HSCs, leading to the identification of CD99 as an antigen selectively expressed on LSCs. Moreover, novel monoclonal antibodies against CD99 exerted significant cytotoxic effects against AML and MDS stem cells.  Recently, we identified CD97 as an antigen expressed in the vast majority of human AMLs. CD97 regulates migration of normal hematopoietic cells as well as the invasive properties of solid cancers, but little is known about its function in AML. Our studies have revealed several features of CD97 that make it particularly important with in AML including: 1) CD97 is one of the most commonly expressed human AML antigens; 2) CD97 promotes blast growth and survival, and limits differentiation; 3) CD97 regulates LSC function, as demonstrated in serial and limiting dilution transplant experiments, but is not required for HSC function; 4) Consistent with the critical role CD97 in AML, CD97 is an independent prognostic variable for overall survival (OS) in both univariate and multivariate analyses. Lastly, novel monoclonal and synthetic antibodies against CD97 appear to exhibit significant anti-leukemic effect, making CD97 a viable therapeutic target.