Page 179 - Haematologica May 2020

Hodgkin Lymphoma
An intronic deletion in megakaryoblastic leukemia 1 is associated with hyperproliferation of B cells in triplets with Hodgkin lymphoma
Ferrata Storti Foundation
Haematologica 2019 Volume 105(5):1339-1350
Julien Record,1* Anton Sendel,1* Joanna S. Kritikou,1 Nikolai V. Kuznetsov,1 Hanna Brauner,1 Minghui He,1 Noemi Nagy,1 Mariana M.S. Oliveira,1 Elena Griseti,1 Christoph B. Haase,1 Jenny Dahlström,2 Sanjaykumar Boddul,2 Fredrik Wermeling,2 Adrian J. Thrasher,3 Chaohong Liu,4 John Andersson,1,5 Hans-Erik Claesson,2 Ola Winqvist,2 Siobhan O. Burns,6,7 Magnus Björkholm2 and Lisa S. Westerberg1
1Department of Microbiology, Tumor and Cell Biology, Biomedicum, Karolinska Institutet, Stockholm, Sweden; 2Department of Medicine Solna, Karolinska University Hospital, Stockholm, Sweden; 3Institute of Child Health, University College London, London, UK; 4Department of Pathogen Biology, School of Basic Medicine, Huazhong University of Science and Technology, Wuhan, China; 5Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; 6Institute of Immunity and Transplantation, University College London, London, UK and 7Department
of Immunology, Royal Free London NHS Foundation Trust, London, UK
* JR and AS contributed equally to this work
ABSTRACT
Megakaryoblastic leukemia 1 (MKL1) is a coactivator of serum response factor and together they regulate transcription of actin cytoskeleton genes. MKL1 is associated with hematologic malig- nancies and immunodeficiency, but its role in B cells is unexplored. Here we examined B cells from monozygotic triplets with an intronic deletion in MKL1, two of whom had been previously treated for Hodgkin lymphoma (HL). To investigate MKL1 and B-cell responses in the pathogenesis of HL, we generated Epstein-Barr virus-transformed lymphoblastoid cell lines from the triplets and two controls. While cells from the patients with treat- ed HL had a phenotype close to that of the healthy controls, cells from the undiagnosed triplet had increased MKL1 mRNA, increased MKL1 protein, and elevated expression of MKL1-dependent genes. This profile was asso- ciated with elevated actin content, increased cell spreading, decreased expression of CD11a integrin molecules, and delayed aggregation. Moreover, cells from the undiagnosed triplet proliferated faster, displayed a higher proportion of cells with hyperploidy, and formed large tumors in vivo. This phenotype was reversible by inhibiting MKL1 activity. Interestingly, cells from the triplet treated for HL in 1985 contained two subpopulations: one with high expression of CD11a that behaved like con- trol cells and the other with low expression of CD11a that formed large tumors in vivo similar to cells from the undiagnosed triplet. This implies that pre-malignant cells had re-emerged a long time after treatment. Together, these data suggest that dysregulated MKL1 activity participates in B-cell transformation and the pathogenesis of HL.
Introduction
Hodgkin lymphoma (HL) is a B-cell malignancy of largely unknown etiology. Familial clustering and twin concordance are seen, as are links with viral infections such as Epstein-Barr virus (EBV).1,2 The malignant HL Reed-Sternberg cells have fre- quently undergone class switch recombination and likely originate from germinal center B cells that fail to undergo apoptosis despite destructive somatic mutations.1,3,4 Various studies have shown the ability of EBV to rescue crippled germinal center B cells from apoptosis, supporting the role of this virus in the pathogenesis of HL.5,6
Megakaryoblastic leukemia 1 (MKL1; also known as MRTF-A, MAL, or BSAC) is
Correspondence:
LISA WESTERBERG
lisa.westerberg@ki.se
Received: March 7, 2019. Accepted: September 26, 2019. Pre-published: October 3, 2019.
doi:10.3324/haematol.2019.216317
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