Systems medicine dissection of chr1q-amp reveals a novel PBX1-FOXM1 axis for targeted therapy in multiple myeloma

Abstract

Understanding the biological and clinical impact of copy number aberrations (CNA) for the development of precision therapies in cancer remains an unmet challenge. Genetic amplification of chromosome 1q (chr1q-amp) is a major CNA conferring adverse prognosis in several types of cancer, including in the blood cancer multiple myeloma (MM). Although several genes across chr1q portend high-risk MM disease, the underpinning molecular aetiology remains elusive. Here, with reference to the 3D chromatin structure, we integrate MM patient multi-omics datasets with genetic variables to obtain an associated clinical risk map across chr1q and to identify 103 adverse prognosis genes in chr1q-amp MM. Prominent amongst these genes, the transcription factor PBX1 is ectopically expressed by genetic amplification and epigenetic activation of its own preserved 3D regulatory domain. By binding to reprogrammed super-enhancers, PBX1 directly regulates critical oncogenic pathways and a FOXM1-dependent transcriptional programme. Together, PBX1 and FOXM1 activate a proliferative gene signature which predicts adverse prognosis across multiple types of cancer. Notably, pharmacological disruption of the PBX1-FOXM1 axis with existing agents (thiostrepton) and a novel PBX1 small-molecule inhibitor (T417) is selectively toxic against chr1q-amplified myeloma and solid tumour cells. Overall, our systems medicine approach successfully identifies CNA-driven oncogenic circuitries, links them to clinical phenotypes and proposes novel CNA-targeted therapy strategies in multiple myeloma and other types of cancer.

Functional transcriptomic landscape informs novel therapeutic strategies in multiple myeloma

“…Among TFs, FOXM1 had highest enrichment score associated with sensitivity to a number of drugs of different classes: DOX, the mTOR inhibitor INK128, PANO, pomalidomide (POM), lenalidomide (LEN) and the PLK1 inhibitor volasertib (VOLA). These results are consistent with FOXM1 being an important regulator of drug resistance in MM 47 . Further, as an indication of the speci city of this unsupervised hypothesis-generating approach, we compared VOLA and BI2536: both are inhibitors of PLK1, a key regulator of cell cycle that phosphorylates FOXM1 that, in turn, regulates PLK1 expression 48,49 .…”

Multiple myeloma with high-risk cytogenetics and its treatment approach

“…The simultaneous enhanced function of the expressed genes of the 1q21 amplicon may affect the resistance of different drugs. Recent studies have indicated that MM cells with 1q21 + seem to be more sensitive to inhibitory agents of MCL1 [ 74 ] and the PBX1-FOXM1 axis [ 75 ] compared with those lacking 1q21 + .…”

Increased Expression of SETDB1 Predicts Poor Prognosis in Multiple Myeloma

“…Marchesini et al [ 8 ] found seventy-eight 1q21 genes either amplified or overexpressed by integrating 246 matched MM samples. Also, 103 candidate genes, located in chromosome 1q, were identified as prominent drivers of chr1q-amp multiple myeloma [ 13 ]. As a result, twenty-eight genes were both detected, including MCL1, ILF2, ADAR, CKS1B, and SETDB1 (supplemental Figure 1A ).…”

“…SETDB1 is mapped to human chromosome 1q21.3, one of seventy-eight amplified or overexpressed 1q21 genes by integrating GISTIC2 and expression data from 246 matched MM samples [ 8 ]. Also, systems medicine dissection of chr1q-amp identified 103 candidate genes, including SETDB1, as adverse prognostic biomarkers combined genomic, epigenomic, and transcriptomic data with genetic variables in MM [ 13 ]. Besides, the relationship between SETDB1 expression and its prognostic values in multiple myeloma has not been studied.…”