A pluripotency signature predicts histologic transformation and influences survival in follicular lymphoma patients.
Histologic transformation (HT) of follicular lymphoma 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 network of gene transcriptional modules underlies HT. Central to the network hierarchy is a signature strikingly enriched for pluripotency-related genes. These genes are typically expressed in embryonic stem cells (ESCs), 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 2 independent patient cohorts and was predictive of propensity of follicular lymphoma tumors to transform. Transformation was associated with an expression signature combining high expression of ESC transcriptional programs with reduced expression of stromal programs. 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.
Gentles
Andrew J
AJ
Department of Radiology, Stanford University School of Medicine, Lucas Center for MR Spectroscopy and Imaging, Stanford, CA 94305, USA. andrewg@stanford.edu
Alizadeh
Ash A
AA
Lee
Su-In
SI
Myklebust
June H
JH
Shachaf
Catherine M
CM
Shahbaba
Babak
B
Levy
Ronald
R
Koller
Daphne
D
Plevritis
Sylvia K
SK
D000818:Animals; D002453:Cell Cycle; D002454:Cell Differentiation; D004195:Disease Models, Animal; D053595:Embryonic Stem Cells / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008224:Lymphoma, Follicular / Q000235:genetics / Q000378:metabolism* / Q000401:mortality* / Q000473:pathology; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics / Q000378:metabolism* / Q000401:mortality* / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D039904:Pluripotent Stem Cells / Q000378:metabolism* / Q000473:pathology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
D016271:Proto-Oncogene Proteins c-myc