Retinoid receptors are transcription factors that play important roles regulating self-renewal and maturation of bone marrow cells, and can be changed from transcriptionally inactive states, to transcriptionally active states, by the presence of a retinoid ligand. The distribution and regulation of natural retinoid ligands is unknown. There are only two FDA approved applications for retinoid therapy in hematology (all-trans retinoic acid for acute promyelocytic leukemia, and bexarotene for cutaneous T cell lymphoma). Other attempts to integrate retinoid-based therapy into clinical hematology have been done through empiric testing, and have not been informed by a rational understanding of retinoid biology in bone marrow cells. We have developed a novel in vivo retinoid reporter assay, to determine which bone marrow cells are exposed to natural retinoids, and whether these are regulated by physiologic or pathologic stress. Unexpectedly, we have found that RXRA, but not RARA or RARG, natural retinoids are present in mouse bone marrow cells, and that these exist intracellularly in myeloid and erythroid progenitor cells, but not in stem cells. In this study, we will further define the distribution and regulation of natural retinoids in bone marrow cells in response to physiologic hematopoietic stressors (e.g. response to cytokines or recovery from cytopenias). We will determine, in which cells natural retinoids are present, and when. We will further determine whether retinoids exist intracellularly following pathologic stress (e.g. leukemia). We will determine whether natural retinoids exists in mature leukemias (monocytic and erythroleukemias) vs immature leukemias, whether this might render these forms of AML sensitive to retinoid agonists vs antagonists, and whether response could be augmented in specific forms of leukemia by inhibition of intracellular or niche-based retinoid elimination. Finally, we will identify what these natural RXR ligands are. These studies will illuminate the mechanism of retinoid sensitivity vs resistance in bone marrow cells, and will help guide the integration of retinoid therapy into clinical hematology.
The long term goal of this project is to define the function and regulation of retinoid receptors, transcription factors that influence bone marrow cell self-renewal and maturation decisions. This will allow us to better predict which blood diseases may be amenable to treatment using retinoid-based differentiation agents.
|Spencer, David H; Russler-Germain, David A; Ketkar, Shamika et al. (2017) CpG Island Hypermethylation Mediated by DNMT3A Is a Consequence of AML Progression. Cell 168:801-816.e13|
|Duncavage, Eric J; Uy, Geoffrey L; Petti, Allegra A et al. (2017) Mutational landscape and response are conserved in peripheral blood of AML and MDS patients during decitabine therapy. Blood 129:1397-1401|
|Ali, Alaa M; Weisel, Daniel; Gao, Feng et al. (2017) Patterns of infectious complications in acute myeloid leukemia and myelodysplastic syndromes patients treated with 10-day decitabine regimen. Cancer Med 6:2814-2821|
|Ali, Alaa M; Jacoby, Meagan; Welch, John S (2016) Hand-foot syndrome following decitabine. Ann Hematol 95:535-6|
|Niu, H; Chacko, J; Hadwiger, G et al. (2015) Absence of natural intracellular retinoids in mouse bone marrow cells and implications for PML-RARA transformation. Blood Cancer J 5:e284|