In myeloid malignancies, morbidity and response to therapy are strongly affected by impairment of normal hematopoiesis, and yet the cellular and molecular mechanisms underlying this phenomenon are poorly understood. During my graduate work, I studied the bone marrow microenvironment (BME) in a syngeneic mouse model of acute myeloid leukemia, in which I demonstrated dramatic osteoblastic defects. Since abundant evidence has supported the central role of osteoblastic lineage cells in hematopoietic stem cell (HSC) regulation, these data identify the leukemia-dependent inhibition of osteoblastic cells as a potential clinical target. Further, we discovered leukemic production of the chemokine CCL3 that has been recently demonstrated to inhibit osteoblastic function in the setting of multiple myeloma. With the long-term goal of identifying the specific cellular and molecular mechanisms responsible for leukemia-dependent osteoblastic inhibition, the current proposal aims to establish the necessity of CCL3 for the inhibition of osteoblastic cells in myeloid malignancies. We hypothesize that production of the chemokine CCL3 by malignant myeloid cells is a critical factor in the negative regulation of osteoblastic cells, and subsequent loss of mineralized bone in myeloid leukemia. Using 2 murine models of myeloid malignancies, primary human AML samples, as well as a novel method of isolation of osteoblastic cells from spicules in normal and leukemic human bone marrow samples, we propose to define the necessity of CCL3 as the mediator of leukemia-induced osteoblastic inhibition using loss of function and pharmacologic approaches both in vivo and in vitro. Data from this project would identify potential therapeutic targets in the treatment of myeloid malignancies. Agents inhibiting CCL3 signaling are currently in clinical development allowing for rapid translation into the clinic.
Hematopoietic stem cells, HSCs, are at the apex of the hematopoietic hierarchy and their function is highly regulated through interactions with the surrounding bone marrow microenvironment, or niche, particularly osteoblastic cells. In myelogenous malignancies such as acute myelogenous leukemia, AML, osteoblastic cells are highly dysregulated, and loss of normal hematopoiesis is major cause of morbidity and mortality. We hypothesize that CCL3 is a critical mediator of osteoblastic inhibition and that by disrupting CCL3 signaling in the setting of myeloid leukemias osteoblastic function can be restored.
| Alwaseem, Hanan; Frisch, Benjamin J; Fasan, Rudi (2018) Anticancer activity profiling of parthenolide analogs generated via P450-mediated chemoenzymatic synthesis. Bioorg Med Chem 26:1365-1373 |
