Acute myeloid leukemia (AML) and the myelodysplastic syndromes (MDS) are initiated and sustained by self-renewing stem cells. These cells often persist in the face of current standard therapies, and they likely represent the reservoir of disease that promotes therapeutic resistance and disease relapse. Cell surface proteins uniquely expressed on these stem cells may allow for therapies that specifically target diseased cells and not normal hematopoietic stem cells. Through transcriptional profiling followed by flow cytometric validation, CD99 was identified as a cell surface marker highly expressed on MDS hematopoietic stem cells (MDS HSCs) and AML leukemic stem cells (LSCs). Monoclonal antibodies (mAbs) targeting CD99 are directly toxic to disease cells in vitro and in vivo, and this cytotoxicity is associated with rapid activation of Src-family kinases (SFKs). CD99 also has significant clinical potential as a biomarker of chemosensitivity. Leveraging our expertise in hematopoietic stem cell biology and developmental therapeutics, we aim to:
Aim 1 : Determine the clinical potential of CD99 as a therapeutic target and prognostic biomarker. We will test the ability of anti-CD99 mAbs to deplete AML LSCs and MDS HSCs in robust pre-clinical disease models, and we will identify the spectrum of AML and MDS subtypes most likely to respond to these therapies. We will analyze clinically annotated gene expression data sets to determine if CD99 expression can be used as a biomarker of chemosensitivity.
Aim 2 : Identify molecular mechanisms of anti-CD99 mAb induced cytotoxicity. We will characterize signaling pathways regulated by CD99 that contribute to CD99-mediated cytotoxicity. We will use proteomic platforms to identify CD99 interacting partners that are functionally required for the cytotoxic effects of anti-CD99 mAbs. These studies promise to contribute towards the development of clinical therapeutics directed against CD99 or its associated biologic pathways, as well as the use of CD99 as a clinically relevant biomarker. Stephen S. Chung, MD is the principal investigator on this proposal and is a practicing medical oncologist with a clinical focus in the myelodysplastic syndromes. He is an Instructor at Memorial Sloan Kettering Cancer Center (MSKCC) and was a postdoctoral fellow from 2010-2016 in the laboratory of Christopher Y. Park, MD PhD, an expert in normal and malignant hematopoietic stem cell biology. He is currently working to translate his findings to the clinic under the mentorship of Ross L. Levine, MD, a world leader in developing novel therapies for myeloid malignancies. In this proposal Dr. Chung outlines a five-year career development plan composed of research, coursework, seminars, and an expert advisory committee. This plan will leverage the rich institutional resources and mentorship at MSKCC to enable him to transition to his own independent laboratory research program and be competitive for R01 funding by the second year of this award.
Acute myeloid leukemia (AML) and the myelodysplastic syndromes (MDS) are disorders of the bone marrow primarily encountered in the elderly that cause significant morbidity and mortality. The prognosis of patients with AML and MDS remains quite poor, and this is in large part attributable to disease stem cells that resist current standard therapies. Our studies have identified CD99 as a protein that is present on AML and MDS stem cells but not normal stem cells, and this grant aims to study the mechanisms by which targeting CD99 may eradicate disease stem cells and provide potentially curative therapies for patients with these diseases.
|Chung, Stephen S; Park, Christopher Y (2017) Aging, hematopoiesis, and the myelodysplastic syndromes. Hematology Am Soc Hematol Educ Program 2017:73-78|
|Chung, Stephen S; Eng, William S; Hu, Wenhuo et al. (2017) CD99 is a therapeutic target on disease stem cells in myeloid malignancies. Sci Transl Med 9:|
|Chung, Stephen S; Park, Christopher Y (2017) Aging, hematopoiesis, and the myelodysplastic syndromes. Blood Adv 1:2572-2578|