This proposal describes a research plan into the role of bone marrow microenvironment in modulating retinoid homeostasis with implications for both normal as well as malignant hematopoiesis and a training program to develop the principal investigator, Dr. Gabriel Ghiaur from a junior faculty into an independent physician-scientist. Dr. Ghiaur studied normal hematopoiesis as a graduate student in the laboratory of Dr. David Williams and then as a post-doctoral fellow in the laboratory of Dr. Jose Cancelas at Cincinnati Children's Hospital. As a hematology fellow in the laboratory of Dr. Richard Jones, Johns Hopkins University, he focused on the role of retinoic acid (RA) in hematopoiesis. Dr. Jones was the first investigator to identify retinaldehyde dehydrogenase as a marker of normal and malignant hematopoietic stem cell and is a recognized expert in the field. Upon completion of his clinical and research fellowship, Dr. Ghiaur has joined the Hematological Malignancies division, at Johns Hopkins in July 2013 as an Instructor and was recently promoted to Assistant Professor of Oncology and Medicine. This laboratory based tenure track position assure Dr. Ghiaur 80% protected time for research and this grant will support his goal of pursuing a career as a laboratory based translational researcher in hematologic malignancies. Regulation of hematopoietic stem cell (HSC) function during steady state conditions as well as during disease states is an area of intense research. Multiple cell-intrinsic and environmental cues have been proposed to connect physiological needs and stem cell behavior. Studies comparing HSC with their more committed progenitor cells, revealed RA as a potential regulator of HSC function. To this end, HSCs appear posed to differentiate if not protected by a RA-low niche maintained via stromal expression of CYP26, a RA- metabolizing enzyme. Thus, modulations of CYP26 expression by inflammatory signals for instance could change RA levels in the niche and thus, adjust HSC behavior to respond to hematological stress. More so, since RA therapies have revolutionized the treatment of acute promyelocytic leukemia but unfortunately had no impact on other hematological malignancies, tempering with stromal CYP protective mechanisms could expand the clinical applications of differentiation therapies. A better understanding of niche drug metabolizing properties and how they change during hematological stress and during therapy is needed to before the develop CYP inhibitors as clinical tools in hematology. The overarching hypothesis of the proposed research is that P450 enzymes expressed by various hematopoietic microenvironments create drug-free sanctuaries in the bone marrow and modulate HSC homeostasis as well as chemotherapy resistance. This proposal aims to: 1) Determine how the bone marrow niche controls RA bioavailability to modify HSC behavior; specifically what stem cell niche (endothelial, mesenchymal or endosteal) depends on CYP26 activity to maintain human HSC, how the local (niche) control of RA levels compares to systemic (hepatic) metabolism and how RA metabolism changes during hematological stress. 2) Study the effects of stromal cytochrome P450 on drug resistance, initially as it relates to resistance RA therapy and then as it relates to chemotherapy in general. The investigators hypothesize that a sophisticated understanding of local drug metabolism will aid in designing optimal strategies to bypass the chemical barriers posed by stromal drug metabolizing enzymes and thus, opening the malignant stem cell niche to systemic chemotherapy.
Making blood (hematopoiesis) is a highly controlled process able to adapt to increased needs in situations of crisis (such as during an infection or after bleeding) and failure of these checks and balances may result in blood cancers. Vitamin A can restore order in unique type of blood cancer called acute promyelocytic leukemia. The current proposal studies how vitamin A controls hematopoiesis and how we can expand the role of vitamin A to restore order in other blood cancers not only in acute promyelocytic leukemia.
|Alonso, Salvador; Jones, Richard J; Ghiaur, Gabriel (2017) Retinoic acid, CYP26, and drug resistance in the stem cell niche. Exp Hematol 54:17-25|
|Ghiaur, Gabriel; Levis, Mark (2017) Mechanisms of Resistance to FLT3 Inhibitors and the Role of the Bone Marrow Microenvironment. Hematol Oncol Clin North Am 31:681-692|
|Alonso, Salvador; Hernandez, Daniela; Chang, Yu-Ting et al. (2016) Hedgehog and retinoid signaling alters multiple myeloma microenvironment and generates bortezomib resistance. J Clin Invest 126:4460-4468|
|Alonso, Salvador; Su, Meng; Jones, Jace W et al. (2015) Human bone marrow niche chemoprotection mediated by cytochrome P450 enzymes. Oncotarget 6:14905-12|
|Deng, Kai; Pertea, Mihaela; Rongvaux, Anthony et al. (2015) Broad CTL response is required to clear latent HIV-1 due to dominance of escape mutations. Nature 517:381-5|
|Su, Meng; Alonso, Salvador; Jones, Jace W et al. (2015) All-Trans Retinoic Acid Activity in Acute Myeloid Leukemia: Role of Cytochrome P450 Enzyme Expression by the Microenvironment. PLoS One 10:e0127790|