2. Academic Validation
  3. Systems medicine dissection of chr1q-amp reveals a novel PBX1-FOXM1 axis for targeted therapy in multiple myeloma

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

  • Blood. 2022 Mar 31;139(13):1939-1953. doi: 10.1182/blood.2021014391.
Nikolaos Trasanidis 1,  Alexia Katsarou 1 2,  Kanagaraju Ponnusamy 1,  Yao-An Shen 3 4 5 6 7,  Ioannis V Kostopoulos 1 8,  Bien Bergonia 1,  Keren Keren 1,  Paudel Reema 9,  Xiaolin Xiao 1,  Richard M Szydlo 1,  Pierangela M R Sabbattini 1,  Irene A G Roberts 10 11,  Holger W Auner 1 2,  Kikkeri N Naresh 2 9,  Aristeidis Chaidos 1 2,  Tian-Li Wang 3 4 5 6,  Luca Magnani 12,  Valentina S Caputo 1 13,  Anastasios Karadimitris 1 2
Affiliations

Affiliations

  • 1 Hugh and Josseline Langmuir Centre for Myeloma Research, Centre for Haematology, Department of Immunology and Inflammation, Imperial College London, London, United Kingdom.
  • 2 Department of Haematology, Hammersmith Hospital, Imperial College Healthcare NHS Foundation Trust, London, United Kingdom.
  • 3 Department of Pathology.
  • 4 Department of Oncology.
  • 5 Department of Gynecology and Obstetrics, and.
  • 6 Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD.
  • 7 Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
  • 8 Department of Biology, School of Science, National and Kapodistrian University of Athens, Athens, Greece.
  • 9 Imperial Experimental Cancer Medicine Centre and Cancer Research UK Imperial Centre, London, United Kingdom.
  • 10 Department of Paediatrics and Medical Research Council Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Oxford University, Oxford, United Kingdom.
  • 11 Oxford Biomedical Research Centre Blood Theme, National Institute for Health Research Oxford Biomedical Centre, Oxford, United Kingdom.
  • 12 Department of Surgery and Cancer, Imperial College London, London, United Kingdom; and.
  • 13 Cancer Biology and Therapy Laboratory, School of Applied Science, London South Bank University, London, United Kingdom.
PMID: 35015835 DOI: 10.1182/blood.2021014391
Abstract

Understanding the biological and clinical impact of copy number aberrations (CNAs) on the development of precision therapies in Cancer remains an unmet challenge. Genetic amplification of chromosome 1q (chr1q-amp) is a major CNA conferring an adverse prognosis in several types of Cancer, including in the blood Cancer multiple myeloma (MM). Although several genes across chromosome 1 (chr1q) portend high-risk MM disease, the underpinning molecular etiology remains elusive. Here, with reference to the 3-dimensional (3D) chromatin structure, we integrate multi-omics data sets from patients with MM with genetic variables to obtain an associated clinical risk map across chr1q and to identify 103 adverse prognosis genes in chr1q-amp MM. Prominent among 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 superenhancers, PBX1 directly regulates critical oncogenic pathways and a FOXM1-dependent transcriptional program. Together, PBX1 and FOXM1 activate a proliferative gene signature that 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-amp myeloma and solid tumor 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 MM and Other types of Cancer.

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