Hypoxia Promotes Dissemination and Colonization in New Bone Marrow Niches in Waldenstrom Macroglobulinemia

Waldenstrom macroglobulinemia, a rare and indolent type of non-Hodgkin lymphoma, is characterized by widespread lymphoplasmacytic B cells in the bone marrow. Previous studies have shown that hypoxic conditions play a key role in the dissemination of other hematologic malignancies. In this study, the effect of hypoxia was tested on the progression and spread of Waldenstrom macroglobulinemia. Interestingly, tumor progression correlated with hypoxia levels in Waldenstrom macroglobulinemia cells and other cells in the bone marrow and correlated with the number of circulating tumor cells in vivo. Mechanistic studies demonstrated that hypoxia decreased cell progression and cell cycle, did not induce apoptosis, and reduced the adhesion between Waldenstrom macroglobulinemia cells and bone marrow stroma, through downregulation of E-cadherin expression, thus explaining increased egress of Waldenstrom macroglobulinemia cells to the circulation. Moreover, hypoxia increased the extravasation and homing of Waldenstrom macroglobulinemia cells to new bone marrow niches in vivo, by increased CXCR4/SDF-1-mediated chemotaxis and maintaining the VLA4-mediated adhesion. Re-oxygenation of hypoxic Waldenstrom macroglobulinemia cells enhanced the rate of proliferation and cell cycle progression and restored intercellular adhesion between Waldenstrom macroglobulinemia cells and bone marrow stroma. This study suggests that targeting hypoxic response is a novel strategy to prevent dissemination of Waldenstrom macroglobulinemia. (C) 2014 AACR.