RT Journal Article
SR Electronic
T1 Genetic program activity delineates risk, relapse, and therapy responsiveness in Multiple Myeloma
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.04.01.012351
DO 10.1101/2020.04.01.012351
A1 Matthew A. Wall
A1 Serdar Turkarslan
A1 Wei-Ju Wu
A1 Samuel A. Danziger
A1 David J. Reiss
A1 Mike J. Mason
A1 Andrew P. Dervan
A1 Matthew W.B. Trotter
A1 Douglas Bassett
A1 Robert M. Hershberg
A1 Adrián López García de Lomana
A1 Alexander V. Ratushny
A1 Nitin S. Baliga
YR 2020
UL http://biorxiv.org/content/early/2020/04/01/2020.04.01.012351.abstract
AB Despite recent advancements in the treatment of multiple myeloma (MM), nearly all patients ultimately relapse and many become refractory to their previous therapies. Although many therapies exist with diverse mechanisms of action, it is not yet clear how the differences in MM biology across patients impacts the likelihood of success for existing therapies and those in the pipeline. Therefore, we not only need the ability to predict which patients are at high risk for disease progression, but also a means to understand the mechanisms underlying their risk. We hypothesized that knowledge of the biological networks that give rise to MM, specifically the transcriptional regulatory network (TRN) and the mechanisms by which mutations impact gene regulation, would enable improved predictions of disease progression and actionable insights for treatment. Here we present a method to infer TRNs from multi-omics data and apply it to the generation of a MM TRN that links chromosomal abnormalities and somatic mutations to downstream effects on gene expression via perturbation of transcriptional regulators. We find that 141 genetic programs underlie the disease and that the activity profile of these programs fall into one of 25 distinct transcriptional states. These transcriptional signatures prove to be more predictive of outcomes than do mutations and reveal plausible mechanisms for relapse, including the establishment of an immuno-suppressive microenvironment. Moreover, we observe subtype-specific vulnerabilities to interventions with existing drugs and motivate the development of new targeted therapies that appear especially promising for relapsed refractory MM.