AML-242: Osteoprogenitor Cells, but Not Mature Osteoblasts/Osteocytes that Support AML Growth in the Bone Marrow Microenvironment

Autor: Marina Konopleva, Michael Andreeff, Anudishi Tyagi, Benoit deCrombrugghe, Venkata Lokesh Battula, Stanley Ly, Bin Yuan, Xin Zhou, Vinitha Mary Kuruvilla, Qi Zhang, Fouad El-Dana
Rok vydání: 2020
Předmět:
Zdroj: Clinical Lymphoma Myeloma and Leukemia. 20:S195
ISSN: 2152-2650
DOI: 10.1016/s2152-2650(20)30740-0
Popis: Context We have reported that AML cells induce osteogenic differentiation in MSCs to facilitate AML growth in the bone marrow (BM) (Battula et al. JCI Insight, 2017). However, the effect of AML cells on various osteo-lineage cells in the BM microenvironment is not known. Objective i) To assess the stage-specific subsets of osteoblast lineage induced by AML cells in BME. ii) To investigate the effect of new bone formation using AML patient-derived-xenograft (PDX) mouse model. Design In this study, we used inducible triple transgenic mice with osterix (Osx) or osteocalcin (Ocn) reporter genes with genotype Osx-CreERt2; Ocn-GFP; ROSA-tdTomato to determine the effect of AML cells on various osteo-lineage cells. In addition, we used AML-PDX mouse models to investigate the impact of AML cell growth on new bone formation. Results In transgenic mice implanted with syngenic AML cells, we found a 3-4 fold increase in Osx+ cells, but no significant difference was observed in Ocn+ cells, suggesting AML cells expand osteoprogenitor cells but not mature osteoblasts in the BM. To determine whether the AML growth in the BM is associated with bone volume, we implanted AML-PDX cells (total 10 models) into NSG mice and analyzed femurs by micro-CT and histological analysis. Interestingly, we observed a dramatic increase in cortical bone thickness and new medullary bone formation in ∼50% of the PDX models tested. Interestingly, we found that increase in bone volume is associated with less aggressive PDX models (which takes 4-5 months to reach 90% PB engraftment). Aggressive PDX models (takes only 3-5 weeks to reach 90% PB engraftment) did not develop new bone. Masson-Goldner's trichrome staining confirmed weblike trabecular bone formation in mice with less aggressive PDX models, which was not observed in aggressive AML PDX models. Conclusion Our data suggest that AML cells induce supportive osteoprogenitor-rich niche in the BM. New bone formation in less aggressive AML-PDX models, but not in aggressive models suggests two different molecular mechanisms regulating AML growth in these two models. Finally, the role of osteoprogenitor niche in AML progression needs further investigation. Grant Acknowledgment Leukemia SPORE CDP, Emerson Collective, Golfers Against Cancer, LLS-TRP to VLB. RP to VLB.
Databáze: OpenAIRE
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