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Diffuse large B cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma (NHL) in adults. Onethird to half of people with DLBCL is not cured despite substantial therapy advance. The variability of outcome is associated with prognostic scoring system such as the International Prognostic Index (IPI), which focus on biological features of the host and of the neoplastic cells. However, considerable recent data suggest lymphoma microenvironment contributes to prognosis by affecting lymphoma cell survival and angiogenesis. For example, gene chip from DLBCL tissues revealed a stromal signature that associated with favorable prognosis. This signature is predominantly composed of genes encoding extracellular matrix (ECM) components and modifiers such as laminin, fibronectin, and collagen. Those with a stromal 2 pattern encoding angiogenesis-related genes are unfavorable. Matrix metalloproteinase-9 (MMP-9) regulates tumor microenvironment by degrading ECM and collagen typeIV, disrupting the physical barrier to facilitate cancer cell invasion. MMP9 is over-expressed in high-grade NHL, associated with an unfavorable prognosis in DLBCL. SB3CT, a potent gelatinase inhibitor against MMP-9/ MMP-2, inhibits angiogenesis, prevents formation of lymphatic vessels, and reduces the spread of lymphoma cells in a mouse T cell lymphoma model. However, little is known of how MMP-9 regulates the lymphoma microenvironment. In a prior study through a proteomic approach, we showed that protease nexin-1 (PN-1) is susceptible to MMP-9-mediated degradation in the prostate cancer microenvironment. PN-1, a 43 kDa serine protease inhibitor, prevents several key micro-environmental proteases including urokinase plasminogen activator (uPA, encoded by PLAU), tissue plasminogen activator (tPA), thrombin, and plasmin. High levels of MMP-9 and uPA are associated with disease progression and an unfavorable prognosis in several human solid cancers. Although deregulation of PN-1 occurs in several solid cancers, the role if any, of PN-1 in hematological cancers is unknown. The coincidence of MMP9 and PLAU gene found in the DLBCL stromal 1 signature suggests a possible link between expression of these genes and the lymphoma microenvironment. First, low levels of PN-1 were found in lymphoid tissues (lymph nodes and spleen) infiltrated with DLBCL cells compared with controls (Fig. 1a). High transcript levels of MMP9 were found in the DLBLC-infiltrated tissues, consistent with prior reports and gene chip data. In contrast, PN1 transcript levels in DLBCL-infiltrated tissues were significantly lower compared with reactive lymph nodes (Fig. 1b). Interestingly, in contrast to the low transcript levels of PN1 in the DLBCL-infiltrated bone marrow, bone marrow from subjects with DLBCL without bone marrow involvement had high levels of PN1 transcripts (Fig. 1c). Thus, PN-1 levels appear reduced in B cell lymphoma. To determine how PN-1 affects the biology of lymphoma cells, we examined endogenous PN1 transcript levels in a number of human B cell lymphoma cell lines (Figure S1A). In contrast to low PN1 expression, MMP9 transcript levels were highest in Raji cells (derived from

Protease nexin-1 prevents growth of human B cell lymphoma via inhibition of sonic hedgehog signaling