New therapeutic opportunities from dissecting the pre-B leukemia bone marrow microenvironment.
Laurence C CheungJennifer TicknerAnastasia M HughesPatrycja SkutMeegan HowlettBree FoleyJoyce OommenJulia E WellsBo HeSajla SinghGrace-Alyssa ChuaJette FordCharles G MullighanRishi Sury KotechaUrsula R KeesPublished in: Leukemia (2018)
The microenvironments of leukemia and cancer are critical for multiple stages of malignancies, and they are an attractive therapeutic target. While skeletal abnormalities are commonly seen in children with acute lymphoblastic leukemia (ALL) prior to initiating osteotoxic therapy, little is known about the alterations to the bone marrow microenvironment during leukemogenesis. Therefore, in this study, we focused on the development of precursor-B cell ALL (pre-B ALL) in an immunocompetent BCR-ABL1+ model. Here we show that hematopoiesis was perturbed, B lymphopoiesis was impaired, collagen production was reduced, and the number of osteoblastic cells was decreased in the bone marrow microenvironment. As previously found in children with ALL, the leukemia-bearing mice exhibited severe bone loss during leukemogenesis. Leukemia cells produced high levels of receptor activator of nuclear factor κB ligand (RANKL), sufficient to cause osteoclast-mediated bone resorption. In vivo administration of zoledronic acid rescued leukemia-induced bone loss, reduced disease burden and prolonged survival in leukemia-bearing mice. Taken together, we provide evidence that targeting leukemia-induced bone loss is a therapeutic strategy for pre-B ALL.
Keyphrases
- bone loss
- bone marrow
- acute myeloid leukemia
- nuclear factor
- acute lymphoblastic leukemia
- mesenchymal stem cells
- induced apoptosis
- stem cells
- toll like receptor
- young adults
- cell cycle arrest
- tyrosine kinase
- immune response
- squamous cell carcinoma
- allogeneic hematopoietic stem cell transplantation
- skeletal muscle
- cell death
- drug induced
- early onset
- metabolic syndrome
- cell proliferation
- postmenopausal women
- inflammatory response
- body composition
- high fat diet induced
- squamous cell