Page 260 - Haematologica March 2020

Ferrata Storti Foundation
Haematologica 2020 Volume 105(3):774-783
Plasma Cell Disorders
The hydroxymethylome of multiple myeloma identifies FAM72D as a 1q21 marker linked to proliferation
Fabrice Chatonnet,1,2,$ Amandine Pignarre,1,2,$ Aurélien A. Sérandour,3-4-5,$ Gersende Caron,1-2 Stéphane Avner,6 Nicolas Robert,7 Alboukadel Kassambara,8 Audrey Laurent,6 Maud Bizot,6 Xabier Agirre,9 Felipe Prosper,9 José I. Martin-Subero,10 Jérôme Moreaux,7,8 Thierry Fest,1,2 and Gilles Salbert6
1Université Rennes 1, Établissement Français du Sang de Bretaggne, Inserm, MICMAC - UMR_S 1236, Rennes, France; 2Laboratoire d'Hématologie, Pôle de Biologie, Centre Hospitalier Universitaire de Rennes, Rennes, France; 3CRCINA, INSERM, CNRS, Université d'Angers, Université de Nantes, Nantes, France; 4Ecole Centrale de Nantes, Nantes, France; 5Institut de Cancérologie de l'Ouest, Site René-Gauducheau, Saint-Herblain, France; 6SPARTE, IGDR, CNRS UMR6290, University Rennes 1, Rennes, France; 7Department of Biological Hematology, CHU Montpellier, Montpellier, France; 8IGH, CNRS, Univ Montpellier, France; 9Area de Oncología, Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, Pamplona, Spain and 10IDIBAPS, Barcelona, Spain
$FC, AP and AAS are co-first authors.
ABSTRACT
Cell identity relies on the cross-talk between genetics and epigenetics and their impact on gene expression. Oxidation of 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC) is the first step of an active DNA demethylation process occurring mainly at enhancers and gene bodies and, as such, participates in processes governing cell identity in nor- mal and pathological conditions. Although genetic alterations are well doc- umented in multiple myeloma (MM), epigenetic alterations associated with this disease have not yet been thoroughly analyzed. To gain insight into the biology of MM, genome-wide 5hmC profiles were obtained and showed that regions enriched in this modified base overlap with MM enhancers and super enhancers and are close to highly expressed genes. Through the def- inition of a MM-specific 5hmC signature, we identified FAM72D as a poor prognostic gene located on 1q21, a region amplified in high risk myeloma. We further uncovered that FAM72D functions as part of the FOXM1 tran- scription factor network controlling cell proliferation and survival and we evidenced an increased sensitivity of cells expressing high levels of FOXM1 and FAM72 to epigenetic drugs targeting histone deacetylases and DNA methyltransferases.
Introduction
MM is a genetically and clinically heterogeneous hematological cancer associated with a limited number of gene translocations into the immunoglobulin heavy chain locus of plasma cells (PC). In particular, CCND1, CCND3, c-MAF, MAFB and MMSET translocations influence prognosis and are used to classify patients into molecular subgroups.1 Genome sequencing studies have revealed considerable het- erogeneity and genomic instability, a complex mutational landscape and a branch- ing pattern of clonal evolution.2,3 Epigenetic modifications including DNA methyla- tion and histone modifications have been also related to MM pathophysiology.4-6 Patients with highly proliferative PC can also show genetic instability of the chro- mosome 1q arm and specially of the pericentromeric region 1q12 and of its imme- diate neighbor 1q21.7,8 Amplification of 1q21, and possibly overexpression of genes lying in 1q21, parallel disease progression.8 However, no causal link between pro- liferation and 1q21 instability has yet been demonstrated, although overexpression of the histone chaperone gene ANP32E, in 1q21.2 and the cyclin-dependent kinase regulator CKS1B, in 1q21.3, is of poor prognosis in MM.9 More recently, ILF2, in 1q21.3, was proposed to be involved in the pathogenic role of 1q21 amplification
Correspondence:
GILLES SALBERT
gilles.salbert@univ-rennes1.fr
THIERRY FEST
thierry.fest@univ-rennes1.fr
JÉRÔME MOREAUX
jerome.moreaux@igh.cnrs.fr
Received: March 15, 2019. Accepted: June 19, 2019. Pre-published: June 20, 2019.
doi:10.3324/haematol.2019.222133
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