129 Waldenström's macroglobulinemia (WM) is an incurable disorder with a lymphoplasmacytic infiltrate in the bone marrow (BM) and IgM monoclonal gammopathy. WM tumor cells show variable differentiation, ranging from mature B-cells to plasma cells, which likely results from failure to fully undergo differentiation. Here we analyzed the expression of several genes involved in B cell differentiation by real time RT-PCR, such as Ets factors, the basic helix-loop-helix (bHLH) E proteins, as well as the inhibitors of DNA binding (Id) proteins which antagonize E protein activity. Comparison of bone marrow CD19+ B cells obtained from 12 untreated WM patients with 15 age-matched healthy donors showed that expression of the Ets factor Spi-B was increased four-fold, while Id2 was decreased three-fold. However, transcript levels of E proteins were similar between these two groups. Furthermore, along with differentiation of primary human CD19+ cells from peripheral blood into CD38+CD20− plasmablasts, Spi-B and Id2 expression levels were significantly decreased and increased, respectively. Ectopic expression of Spi-B in primary human CD19+ cells inhibited the plasma cell differentiation associated with decreased transcription levels of BLIMP1, XBP-1 spliced form, and IRF4. In addition, overexpression of Spi-B in BCWM.1 WM cells also resulted in repressed expression of BLIMP1, XBP-1 spliced form, and IRF4. Conversely, knocking down Spi-B in BCWM.1 WM cells increased IRF4 and Id2 expression. Importantly, in primary WM bone marrow CD19+ cells, knocking down of Spi-B induced CD38+CD20- plasma cell formation and increased expression of BLIMP1, XBP-1 spliced, IRF4, and Id2. Moreover, knocking down Spi-B in primary WM cells decreased Bcl-2 expression. Collectively, our results suggest that Spi-B overexpression plays an essential role in the pathogenesis of WM by repressing factors involved in plasma cell differentiation while promoting tumor cell survival through Bcl-2. Disclosures: No relevant conflicts of interest to declare.