Dominant contribution of malignant endothelial cells to endotheliopoiesis in chronic myeloid leukemia.
ABSTRACT Although it has been well-established that hemangioblasts are present in chronic myeloid leukemia (CML) and contribute to both malignant hematopoiesis and endotheliopoiesis, the real contribution of CML-derived endothelial cells to endotheliopoiesis in CML patients has never been evaluated. The current study sought to determine CML-derived endotheliopoiesis in patients with CML.
Endothelial cells were isolated from the bone marrow or peripheral blood of six newly diagnosed CML patients using an immunomagnetic approach. The resulting endothelial cells were immediately subjected to fluorescence in situ hybridization analysis to determine BCR-ABL-positive endothelial cells.
The purity of isolated endothelial cells was 94.47% +/- 2.37%. In bone marrow, the BCR-ABL-positive endothelial cells accounted for 70.8% +/- 10.7% of total freshly isolated endothelial cells. In peripheral blood, however, the BCR-ABL-positive endothelial cells accounted for only 20.8% +/- 9.8% of isolated endothelial cells.
The present data demonstrate a dominant contribution of CML-derived endothelial cells to endotheliopoiesis in newly diagnosed CML, and provide the rationale for targeting hemangioblasts and angiogenesis in management of CML.
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ABSTRACT: Angiogenesis is increasingly recognized as an important prognosticator associated with the progression of lymphoma and as an attractive target for novel modalities. We report a previously unrecognized mechanism by which lymphoma endothelium facilitates the growth and dissemination of lymphoma by interacting with circulated T cells and suppresses the activation of CD4(+) T cells. Global gene expression profiles of microdissected endothelium from lymphoma and reactive lymph nodes revealed that T cell immunoglobulin and mucin domain-containing molecule 3 (Tim-3) was preferentially expressed in lymphoma-derived endothelial cells (ECs). Clinically, the level of Tim-3 in B cell lymphoma endothelium was closely correlated to both dissemination and poor prognosis. In vitro, Tim-3(+) ECs modulated T cell response to lymphoma surrogate antigens by suppressing activation of CD4(+) T lymphocytes through the activation of the interleukin-6-STAT3 pathway, inhibiting Th1 polarization, and providing protective immunity. In a lymphoma mouse model, Tim-3-expressing ECs promoted the onset, growth, and dissemination of lymphoma by inhibiting activation of CD4(+) T cells and Th1 polarization. Our findings strongly argue that the lymphoma endothelium is not only a vessel system but also a functional barrier facilitating the establishment of lymphoma immune tolerance. These findings highlight a novel molecular mechanism that is a potential target for enhancing the efficacy of tumor immunotherapy and controlling metastatic diseases.Journal of Experimental Medicine 02/2010; 207(3):505-20. DOI:10.1084/jem.20090397 · 13.91 Impact Factor
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ABSTRACT: Chronic myeloid leukemia therapy has remarkably improved with the use of frontline BCR-ABL kinase inhibitors such that newly diagnosed patients have minimal disease manifestations or progression. Effective control of disease may also set the stage for eventual 'cure' of this leukemia. However, the existence of Philadelphia chromosome-positive leukemic cells that are unaffected by BCR-ABL inhibition represents a major barrier that may delay or prevent curative therapy with the current approaches. The most commonly reported mechanism of resistance to tyrosine kinase inhibitor-based therapies involves BCR-ABL gene mutations and amplification, but these changes may not be solely responsible for disease relapse when inhibitor-based therapies are curtailed. Therefore new targets may need to be defined before significant advancement in curative therapies is possible. Emerging evidence suggests that persistence of chronic myeloid leukemia stem cells or acquisition of stem cell-like characteristics prevents complete elimination of chronic myeloid leukemia by tyrosine kinase inhibition alone. This review focuses on several recently emerging concepts regarding the existence and characteristics of chronic myeloid leukemia stem cells. Definitions based on human primary cells and animal model studies are highlighted as are the potential signaling pathways associated with disease repopulating cells. Finally, several recently defined therapeutic targets and active compounds that have emerged from stem cell studies are described. Our goal is to provide an unbiased report on the current state of discovery within the chronic myeloid leukemia stem cell field and to orient the reader to emerging therapeutic targets and strategies that may lead to elimination of this leukemia.Leukemia & lymphoma 02/2011; 52 Suppl 1(S1):60-80. DOI:10.3109/10428194.2010.546921 · 2.89 Impact Factor