Abstract Abstract 3957 Introduction: MicroRNA dysregulation has been described in Waldenstrom's Macroglobulinemia (WM), an indolent non-Hodgkin's lymphoma characterized by the accumulation of IgM secreting lymphoplasmacytic cells (LPC). Whether MicroRNA dysregulation represents a primary oncogenic event, is reactive to an oncogenic event, or is related to the stage of B-cell differentiation remains to be clarified. As part of these efforts, we sought to delineate aberrant MicroRNAs which emerge by direct comparison of WM LPC with memory B-cells, from wherein the WM clone is believed to have emerged. Further to these efforts, we also sought to clarify whether MicroRNA dysregulation is related to the presence of a somatic mutation in MYD88 (L265P), a widely expressed mutation in WM patients, which also induces NF-kB and STAT3 activation via IRAK 1/4 (Nature 2011, 470:115–119). Patients and Methods: CD19+ selected bone marrow cells from WM patients were isolated by immunomagnetic sorting. Healthy donor B-cells (CD19+) were isolated from peripheral blood, and further sorted using a memory B-cell (CD19+ CD27+) isolation kit (Miltenyi, Auburn CA). MicroRNA profiling was performed using Taqman low-density arrays. Taqman stem-loop Real-Time PCR was used for validation of MicroRNA changes. MYD88 L265P expressing BCWM.1 and MWCL-1 cells were used for lentiviral transduction experiments, and inhibitory studies using an IRAK 1/4 kinase inhibitor (407601, EMD, Gibbstown, USA) in order to assess changes in MicroRNA expression. STAT3 and IKKα phosphorylation were detected by Western blot using phospho-specific antibodies. Results: MicroRNA profiling was performed using bone marrow LPC from 11 WM patients, and compared to total B-cells, and selected memory B-cells from 7 healthy donors. Real-time PCR was also performed in 27 additional patients for a total of 38 patients which showed that MicroRNA-21, −155 and −29c were increased, and MicroRNA-9*, −27b, −126, and −145 were decreased when WM LPC were directly compared with total healthy donor CD19+ cells. When WM LPC were directly compared to healthy donor memory B-cells, only MicroRNA-21 and −155 remained significantly higher in WM LPC. To investigate whether MicroRNA-21 and −155 are impacted by the MYD88 L265P mutation, we next performed lentiviral knock-down experiments in BCWM.1 and MWCL-1 cells. Levels of MicroRNA-21 and −155 decreased following knockdown of MYD88, whereas over-expression of MYD88 L265P led to enhanced Micro-RNA 21 expression. In addition, MicroRNA-21 but not −155 decreased following treatment of BCWM.1 and MWCL-1 cells with an IRAK 1/4 kinase inhibitor potentially signifying differences in downstream activation of MicroRNA-21 and −155 by MYD88 L265P. Conclusion: Differences in MicroRNA expression vary based on which population of healthy donor B-cells are compared to WM LPC. Direct comparison of WM LPC to healthy donor memory B-cells reveals differences in MicroRNA-21, and −155. Importantly, MicroRNA-21 and −155 are induced by the MYD88 L265P mutation through distinct signaling pathways. The data suggest a reactive role for MicroRNA-21 and −155 in response to the MYD88 L265P mutation in WM. Disclosures: No relevant conflicts of interest to declare.