Independent Mechanisms Lead to Genomic Instability in Hodgkin Lymphoma: Microsatellite or Chromosomal Instability †.

Corina Cuceu,Sylwia Kabacik,Christophe Badie,Grace Shim,Justyna Mika,Bruno Colicchio,Aude Lenain,Monika Frenzel,Patrice Carde,Eric Jeandidier,Steffen Junker,William Hempel,Radhia M’Kacher,Luc Morat,Joanna Polanska,François Plassa,Mustafa Al Jawhari,Alain Dieterlen,Theodore Girinsky

doi:10.3390/cancers10070233

Abstract

Background: Microsatellite and chromosomal instability have been investigated in Hodgkin lymphoma (HL). Materials and Methods: We studied seven HL cell lines (five Nodular Sclerosis (NS) and two Mixed Cellularity (MC)) and patient peripheral blood lymphocytes (100 NS-HL and 23 MC-HL). Microsatellite instability (MSI) was assessed by PCR. Chromosomal instability and telomere dysfunction were investigated by FISH. DNA repair mechanisms were studied by transcriptomic and molecular approaches. Results: In the cell lines, we observed high MSI in L428 (4/5), KMH2, and HDLM2 (3/5), low MSI in L540, L591, and SUP-HD1, and none in L1236. NS-HL cell lines showed telomere shortening, associated with alterations of nuclear shape. Small cells were characterized by telomere loss and deletion, leading to chromosomal fusion, large nucleoplasmic bridges, and breakage/fusion/bridge (B/F/B) cycles, leading to chromosomal instability. The MC-HL cell lines showed substantial heterogeneity of telomere length. Intrachromosmal double strand breaks induced dicentric chromosome formation, high levels of micronucleus formation, and small nucleoplasmic bridges. B/F/B cycles induced complex chromosomal rearrangements. We observed a similar pattern in circulating lymphocytes of NS-HL and MC-HL patients. Transcriptome analysis confirmed the differences in the DNA repair pathways between the NS and MC cell lines. In addition, the NS-HL cell lines were radiosensitive and the MC-cell lines resistant to apoptosis after radiation exposure. Conclusions: In mononuclear NS-HL cells, loss of telomere integrity may present the first step in the ongoing process of chromosomal instability. Here, we identified, MSI as an additional mechanism for genomic instability in HL.

Highlights

Hodgkin lymphoma (HL) is a unique disease in which the neoplastic Hodgkin andReed–Sternberg (HRS) cells constitute only 1–2% of the tumor tissue, the remaining tumor microenvironment being composed of various inflammatory cells [1]
These results demonstrate the absence of Microsatellite Instability (MSI) in L1236 (0/5), low MSI (MSI-L)
In HL cell lines (95.5% for L428, 95.3% for KMH2, and 92.3% for HDLM2), we found a correlation between MSI and the co-expression of CD30+/CD15+, one of the clinical hallmarks of HL. (Figure S1)

Summary

Introduction

Hodgkin lymphoma (HL) is a unique disease in which the neoplastic Hodgkin andReed–Sternberg (HRS) cells constitute only 1–2% of the tumor tissue, the remaining tumor microenvironment being composed of various inflammatory cells [1]. Genomic instability has been described as a characteristic of HRS cells and a driving force of the aggressiveness of HL [7,8,9]. The mechanisms underlying such genomic instability are still unclear [8]. Microsatellite and chromosomal instability have been investigated in Hodgkin lymphoma (HL). Chromosomal instability and telomere dysfunction were investigated by FISH. Small cells were characterized by telomere loss and deletion, leading to chromosomal fusion, large nucleoplasmic bridges, and breakage/fusion/bridge (B/F/B) cycles, leading to chromosomal instability. Transcriptome analysis confirmed the differences in the DNA repair pathways between the NS and MC cell lines.

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