Circulating microvesicles in B-cell chronic lymphocytic leukemia can stimulate marrow stromal cells: Implications for disease progression

Asish K. Ghosh, Charla R. Secreto, Traci R. Knox, Wei D Ding, Debabrata Mukhopadhyay, Neil Elliot Kay

Research output: Contribution to journalArticle

149 Citations (Scopus)

Abstract

Microvesicles (MVs) released by malignant cancer cells constitute an important part of the tumor microenvironment. They can transfer various messages to target cells and may be critical to disease progression. Here, we demonstrate that MVs circulating in plasma of B-cell chronic lymphocytic leukemia (CLL) patients exhibit a phenotypic shift from predominantly platelet derived in early stage to leukemic B-cell derived at advanced stage. Furthermore, the total MV level in CLL was significantly greater compared with healthy subjects. To understand the functional implication, we examined whether MVs can interact and modulate CLL bone marrow stromal cells (BMSCs) known to provide a "homing and nurturing" environment for CLL B cells. We found that CLL-MV can activate the AKT/mammalian target of rapamycin/p70S6K/hypoxia- inducible factor-1α axis in CLL-BMSCs with production of vascular endothelial growth factor, a survival factor for CLL B cells. Moreover, MV-mediated AKT activation led to modulation of the β-catenin pathway and increased expression of cyclin D1 and c-myc in BMSCs. We found MV delivered phospho-receptor tyrosine kinase Axl directly to the BMSCs in association with AKT activation. This study demonstrates the existence of separate MV phenotypes during leukemic disease progression and underscores the important role of MVs in activation of the tumor microenvironment.

Original languageEnglish (US)
Pages (from-to)1755-1764
Number of pages10
JournalBlood
Volume115
Issue number9
DOIs
StatePublished - Mar 4 2010

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B-Cell Chronic Lymphocytic Leukemia
Stromal Cells
Disease Progression
Bone Marrow
Cells
Bone
Mesenchymal Stromal Cells
Chemical activation
Tumors
Tumor Microenvironment
70-kDa Ribosomal Protein S6 Kinases
Hypoxia-Inducible Factor 1
Catenins
Cyclin D1
Sirolimus
Platelets
Vascular Endothelial Growth Factor A
Modulation
Plasma Cells
Association reactions

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Immunology
  • Hematology

Cite this

Circulating microvesicles in B-cell chronic lymphocytic leukemia can stimulate marrow stromal cells : Implications for disease progression. / Ghosh, Asish K.; Secreto, Charla R.; Knox, Traci R.; Ding, Wei D; Mukhopadhyay, Debabrata; Kay, Neil Elliot.

In: Blood, Vol. 115, No. 9, 04.03.2010, p. 1755-1764.

Research output: Contribution to journalArticle

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