Ash A. Alizadeh, MD/PhD

Publication Details

• A pluripotency signature predicts histological transformation and influences survival in follicular lymphoma patients

  Gentles AJ**, Alizadeh AA** (contributed equally), Lee S, Myklebust JH, Shachaf CM, Shahbaba B, Levy R, Koller D, Plevritis SK.. Blood. 2009

  Histological transformation of follicular (FL) to diffuse large B cell lymphoma (DLBCL-t) is associated with accelerated disease course and drastically worse outcome, yet the underlying mechanisms are poorly understood. We show that a hierarchy of gene transcriptional modules underlies histological transformation (HT), using module network analysis. Central to the network hierarchy is a signature that is strikingly enriched for pluripotency-related genes. These genes are typically expressed in embryonic stem cells (ESC), including MYC and its direct targets. This core ESC-like program was independent of proliferation/cell-cycle and overlapped, but was distinct from, normal B-cell transcriptional programs. Furthermore, we show that the ESC program is correlated with transcriptional programs maintaining tumor phenotype in transgenic MYC-driven mouse models of lymphoma. Although our approach was to identify HT mechanisms, rather than to derive an optimal survival predictor, a model based on ESC/differentiation programs stratified patient outcomes in the training dataset as well as in an independent validation set. The model was also predictive of propensity of FL tumors to transform. Transformation was associated with high expression of ESC transcriptional programs in combination with reduced TGF-beta signaling. Together, these findings suggest a central role for an ESC-like signature in the mechanism of HT and provide new clues for potential therapeutic targets.