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Transl Biomed. Author manuscript; available in PMC 2016 Jan 12.
Published in final edited form as:
Transl Biomed. 2015; 6(2): 14.
PMCID: PMC4710364
NIHMSID: NIHMS723980
PMID: 26770884

Modeling The Bone Marrow Microenvironment’s Influence on Leukemic Disease

R Evans,1 KH Martin,1,2 BS Moses,1 WL Slone,1 I Hare,1,3 D Piktel,1 P Thomas,1 and LF Gibson1,3
Author information Copyright and License information PMC Disclaimer

The bone marrow microenvironment serves as both the site of initiation of the majority of hematopoietic malignancies and also contributes to maintenance of minimal residual disease by promoting biologically relevant changes in tumor cells. These functional alterations of leukemic cells include, but are not limited to modulation of cell cycle [1,2], regulation of anti-apoptotic signaling cascades [3–6], and influence on metabolic activity [7–9]. Of clinical relevance, these pathways impact on therapeutic response, making it critical to have robust in vitro systems to interrogate tumor cell interactions with stromal elements of the microenvironment to screen chemotherapeutic agents and inform the in vivo model design.

To generate a model of the marrow microenvironment niche human leukemic cells were co-cultured with human primary bone marrow stromal cells (BMSC). Frequently, applications require separation of tumor cells and stromal components for subsequent western blot, PCR, DNA or RNA based analysis. However, confocal microscopy provides the unique opportunity to study critical tumor: stromal cell interactions in vitro without physically detaching the tumor population prior to evaluation. This approach is valuable given the transient nature of cell signaling that may be immediately altered upon physical removal of leukemic cells from niche derived stroma. With this approach a variety of targets are amendable to evaluation, with Ki67 shown in Figure 1 as just one example.

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Ki67+ evaluation of human leukemic and bone marrow stromal cells (BMSC). Nalm-27 Ph+ ALL leukemic cells (Fujisaki Cancer Center) co-cultured with a dividing Ki67+ human primary BMSC (A), Nalm-27 cells co-cultured with confluent BMSC representing one structural component of the bone marrow microenvironment (B) and Nalm-27 tumor cells in a 3-dimensional static co-culture with BMSC (C) to model architecture of the niche.

Acknowledgments

Funding Source

NIH NHLBI R01 HL056888 (LFG), NIH NCI R01 CA134573NIH (LFG), P30 GM103488 (LFG), WV CTR-IDEA NIH 1U54 GM104942, the Alexander B. Osborn Hematopoietic Malignancy and Transplantation Program, and the WV Research Trust Fund.

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