New therapies are urgently needed for Acute Myelogenous Leukemia (AML). Treatment-resistant AML cells are evidently protected within bone marrow endosteal niches. This proposal is designed to provide groundwork for the development of new therapies aimed at inhibiting the cellular mechanisms of the bone marrow microenvironment that protect AML cells. We recently found that differentiating osteoblasts, but not the osteoprogenitors or terminally-differentiated osteocytes, are capable of protecting AML cells from apoptosis including that induced by SDF-1 (CXCL12) secreted by other cells in the bone marrow microenvironment. Additionally, our preliminary data indicates that differentiating osteoblasts also protect AML cells from chemotherapeutic-induced apoptosis. Interestingly, our results indicate that an early stage of differentiation of osteoprogenitors towards osteoblasts is crucial to permit these cells to protect AML cells. Inhibition of the specific stage(s) of osteoblat differentiation capable of protecting AML cells from SDF-1- or chemotherapeutic-induced apoptosis might enhance the efficacy of current therapies of AML. Unfortunately, this protective stage of osteoblast differentiation is not clearly defined at present. Here, we propos to use our in vitro co-culture systems and mouse models of AML to test our hypothesis that inhibiting osteoblast differentiation will significantly impair the ability of the endosteal bone marrow niche to protect AML cells.
Our Aims are to 1) Disrupt specific stages of osteoblast differentiation via characterized genetic alterations in order to identify the particular stage(s) f osteoblast development capable of protecting AML cells in in vitro co-culture models of the bone marrow, and to 2) Determine the survival rate and localization of AML cells in mouse bone marrow microenvironments deficient in osteoblast differentiation, and assess the effects on the severity of AML disease and the rate of relapse in these animals. Combined, these studies will test our hypothesis and identify the particular stage(s) of osteoblast differentiation that mediate protection of AML cells from SDF-1- and chemotherapeutic-induced apoptosis.
New therapies are urgently needed for Acute Myelogenous Leukemia (AML). Chemotherapy frequently fails to kill all the AML cancer cells because they are protected within the bone marrow, resulting in relapse. Blocking this protection would greatly improve chemotherapy treatment of AML, but so far, it is not clear how to do this. We recently discovered that not all osteoblasts can protect AML cells, only some 'young' osteoblasts. Here, we propose to more precisely define the osteoblast life stage that promotes AML cell survival in the bone marrow and to determine how to block it.
| Sterner, Rosalie M; Kremer, Kimberly N; Dudakovic, Amel et al. (2018) Tissue-Nonspecific Alkaline Phosphatase Is Required for MC3T3 Osteoblast-Mediated Protection of Acute Myeloid Leukemia Cells from Apoptosis. J Immunol 201:1086-1096 |
| Sterner, Rosalie M; Kremer, Kimberly N; Al-Kali, Aref et al. (2017) Histone deacetylase inhibitors reduce differentiating osteoblast-mediated protection of acute myeloid leukemia cells from cytarabine. Oncotarget 8:94569-94579 |
