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MLL/AF-4 leukemic cells recruit new blood vessels but do not incorporate into capillaries in culture or in a NOD/SCID xenograft model

Leukemia volume 23, pages 990–993 (2009)Cite this article

Tumor angiogenesis plays a critical role in solid tumor development and metastasis. Increased angiogenesis has been implicated in the pathogenesis of hematologic malignancies.1 The blood supply to tumors may be provided through a number of mechanisms, including intussusceptive angiogenesis, recruitment of endothelial progenitor cells, vessel co-option and vasculogenic mimicry. Hemangioblasts are known to generate both hematopoietic and endothelial lineages in early embryonic life. Currently, several studies demonstrate the presence of cells containing clonotypic, cancer-causing mutations within microvessel endothelial cells in certain cancers.2, 3 These findings suggest that certain leukemias originate from bone marrow-derived hemangioblasts or become hemangioblasts that can give rise to both malignant blood cells and endothelial cells. Infant leukemia associated with t(4;11) is particularly aggressive and difficult to cure. Microarray studies showing that t(4;11) leukemia cells have a hemangioblastic phenotype4, 5 suggest that therapy targeting angiogenesis might be a fruitful approach to treating this deadly disease. To determine the potential role of antiangiogenesis therapy in infant leukemia, we investigated whether infant leukemia cells behave like hemangioblasts and produce their own blood vessels as they invade into tissues.

For this purpose, we analyzed the expression of angiogenic cytokines and receptors in mRNA and protein levels in our t(4;11) acute lymphoblastic leukemia cell lines SEM-K2 and RS4;11, and acute myeloid leukemia (AML) cell line MV4–11 and in primary leukemia cells of two pateints with t(4;11) from two patients. We used quantitative real-time reverse transcription PCR to measure the expression levels of endothelial cell- and hemangioblast-related receptors. To standardize the mRNA content, we used glyceraldehyde-3-phosphate dehydrogenase as the endogenous control and human umbilical vascular endothelial cells (HUVECs) as the reference sample. The amount of target relative to reference sample was calculated as 2 - ΔΔ C t , as described earlier.6 As shown in Table 1, we found that t(4;11) leukemia cells expressed mRNA for EPOR at high levels, but expressed that for vWF, Tie-2 and KDR at low levels or beyond detection. MV4–11 expressed EPOR and VE-cadherin at higher levels, whereas RS4;11 expressed CD34 and SEM-K2 vWF at higher levels.

Table 1 Quantifying RNA expression of angiogenic receptors using real-time RT-PCR
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Acknowledgements

This study was supported by a grant from the Pediatric Cancer Foundation. Children's Oncology Group (COG) is acknowledged for providing primary leukemia cell samples from COG ALL Cell Bank. This bank was supported by the COG Chair's Grant no. CA98543 and NIH U24 CA114766.

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Authors and Affiliations

  1. Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL, USA

    Z Hu, X-M Li & W B Slayton

  2. Program in Stem Cell Biology and Regenerative Medicine, University of Florida College of Medicine, Gainesville, FL, USA

    M L Jorgensen

  3. Blood and Marrow Transplant Program, University of Florida College of Medicine, Gainesville, FL, USA

    W B Slayton

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  1. Z Hu
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  2. X-M Li
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Correspondence to W B Slayton.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Hu, Z., Li, XM., Jorgensen, M. et al. MLL/AF-4 leukemic cells recruit new blood vessels but do not incorporate into capillaries in culture or in a NOD/SCID xenograft model. Leukemia 23, 990–993 (2009). https://doi.org/10.1038/leu.2008.345

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