The mechanisms by which a leukemic clone suppresses normal hematopoiesis are poorly understood, and yet this phenomenon likely contributes to disease progression, disease morbidity and response to therapy. Our recent analysis of the bone marrow microenvironment (BME) in a syngeneic mouse model of acute myeloid leukemia1 demonstrated dramatic osteoblastic defects. Since our laboratory and others have demonstrated the central role of osteoblastic lineage cells in hematopoietic stem cell (HSC) regulation, these data identify osteoblastic cells as a potential clinical target to stimulat normal HSC recovery in leukemia and decrease BME support of leukemic stem cells (LSCs). Moreover, we discovered leukemic production of the chemokine CCL3, recently demonstrated to inhibit osteoblastic function in multiple myeloma. With the long-term goal of targeting the HSC and leukemia stem cell (LSC) niches to improve therapy for leukemia and impact disease control, the current proposal aims to efficiently, effectively and safely apply pharmacologic tools currently approved for bone anabolic treatment to leukemia. We hypothesize that 1) leukemia cells decrease the ME support of HSCs and normal hematopoiesis in favor of LSCs and bulk leukemia, promoting disease progression and that 2) interference with leukemia signals disrupting the ME and/or ME stimulation by bone anabolic treatment in the context of leukemia will improve HSC support and decrease LSC competitiveness. Using two murine models as well as a novel method of isolation of osteoblastic cells from spicules in normal and leukemic human bone marrow samples, we propose to: 1.) Define the extent and timing of leukemia-induced osteoblastic lineage inhibition. 2.) Define changes on leukemia-induced ME ability to support normal and malignant hematopoiesis. 3.) Establish the requirement for CCL3 as the mediator of leukemia-induced ME changes using loss of function, overexpression and pharmacologic approaches. 4.) Determine if therapeutic targeting of leukemia-associated osteoblasts impacts normal hematopoiesis, disease progression and LSC function. Data from this project would represent a paradigm shift in the therapy for patients with AML, where targeting of the BME improves our ability to treat the leukemia and more readily restore normal hematopoiesis. Agents stimulating bone forming cells are already available for patient use in the non-malignant scenario allowing for rapid translation into the clinic.
Hematopoietic stem cells, HSCs, are at the apex of the hematopoietic hierarchy and their ability to maintain blood cell production is in part regulated through interactions with the surrounding bone marrow microenvironment, BME, or niche. In diseases of the bone marrow such as acute myelogenous leukemia, AML, the interaction of the normal HSCs and their progeny is altered leading to impaired blood cell production, increased risk of infection, bleeding and the need for transfusions. We hypothesize that CCL3 is a critical mediator of this effect and that by directly targeting the osteoblastic component of the BME, we can enhance recovery of normal bone marrow function in patients with AML and decrease disease related morbidity and mortality.
|Balderman, Sophia R; Li, Allison J; Hoffman, Corey M et al. (2016) Targeting of the bone marrow microenvironment improves outcome in a murine model of myelodysplastic syndrome. Blood 127:616-25|
|Calvi, Laura M; Link, Daniel C (2015) The hematopoietic stem cell niche in homeostasis and disease. Blood 126:2443-51|
|Evans, Andrew G; Calvi, Laura M (2015) Notch signaling in the malignant bone marrow microenvironment: implications for a niche-based model of oncogenesis. Ann N Y Acad Sci 1335:63-77|
|Sivagnanalingam, Umayal; Balys, Marlene; Eberhardt, Allison et al. (2015) Residual Disease in a Novel Xenograft Model of RUNX1-Mutated, Cytogenetically Normal Acute Myeloid Leukemia. PLoS One 10:e0132375|
|Frisch, Benjamin J; Calvi, Laura M (2014) Osteoblasts as leukemia-initiating cells. Bonekey Rep 3:572|
|Frisch, Benjamin J; Calvi, Laura M (2014) Hematopoietic stem cell cultures and assays. Methods Mol Biol 1130:315-24|
|Calvi, Laura M; Link, Daniel C (2014) Cellular complexity of the bone marrow hematopoietic stem cell niche. Calcif Tissue Int 94:112-24|
|Hoffman, Corey M; Calvi, Laura M (2014) Minireview: complexity of hematopoietic stem cell regulation in the bone marrow microenvironment. Mol Endocrinol 28:1592-601|
|Balderman, Sophia R; Calvi, Laura M (2014) Biology of BM failure syndromes: role of microenvironment and niches. Hematology Am Soc Hematol Educ Program 2014:71-6|
|Calvi, Laura M (2013) Osteolineage cells and regulation of the hematopoietic stem cell. Best Pract Res Clin Haematol 26:249-52|