title: Mantle cell lymphoma-variant Richter syndrome: Detailed molecular-cytogenetic and backtracking analysis reveals slow evolution of a pre-MCL clone in parallel with CLL over several years.
abstract: Richter syndrome represents the transformation of the chronic lymphocytic leukemia (CLL) into an aggressive lymphoma, most frequently the diffuse large B-cell lymphoma (DLBCL). In this report we describe a patient with CLL, who developed a clonally-related pleomorphic highly-aggressive mantle cell lymphoma (MCL) after five cycles of a fludarabine-based second-line therapy for the first relapse of CLL. Molecular cytogenetic methods together with whole-exome sequencing revealed numerous gene alterations restricted to the MCL clone (apart from the canonical t(11;14)(q13;q32) translocation) including gain of one copy of ATM gene or emergence of TP53, CREBBP, NUP214, FUBP1 and SF3B1 gene mutations. Similarly, gene expression analysis revealed vast differences between the MCL and CLL transcriptome, including overexpression of cyclin D1, downregulation of cyclins D2 and D3, or downregulation of IL4R in the MCL clone. Backtracking analysis using quantitative PCR specifically detecting an MCL-restricted focal deletion of TP53 revealed that the pre-MCL clone appeared in the bone marrow and peripheral blood of the patient approximately 4 years before the clinical manifestation of MCL. Both molecular cytogenetic and sequencing data support the hypothesis of a slow development of the pre-MCL clone in parallel to CLL over several years, and thereby exclude the possibility that the transformation event occurred at the stage of the CLL relapse clone by mere t(11;14)(q13;q32) acquisition.
authors.affiliation: Department of Hematology, Charles University General Hospital Prague, Prague, Czech Republic. pavel.klener@gmail.com.|Institute of Pathological Physiology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic. pavel.klener@gmail.com.
authors.forename: Pavel
authors.initials: P
authors.lastname: Klener
authors.affiliation: Childhood Leukemia Investigation Prague (CLIP), Faculty Hospital Motol Prague, Prague, Czech Republic.
authors.forename: Eva
authors.initials: E
authors.lastname: Fronkova
authors.affiliation: Center of Oncocytogenetics, Institute of Clinical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
authors.forename: Adela
authors.initials: A
authors.lastname: Berkova
authors.affiliation: Department of Pathology, Charles University General Hospital Prague, Prague, Czech Republic.
authors.forename: Radek
authors.initials: R
authors.lastname: Jaksa
authors.affiliation: Center of Oncocytogenetics, Institute of Clinical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
authors.forename: Halka
authors.initials: H
authors.lastname: Lhotska
authors.affiliation: Department of Hematology, Charles University General Hospital Prague, Prague, Czech Republic.
authors.forename: Kristina
authors.initials: K
authors.lastname: Forsterova
authors.affiliation: Department of Pathology and Molecular Medicine, Second Faculty of Medicine, Faculty Hospital Motol Prague, Prague, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Soukup
authors.affiliation: Institute of Pathological Physiology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
authors.forename: Vojtech
authors.initials: V
authors.lastname: Kulvait
authors.affiliation: Institute of Pathological Physiology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
authors.forename: Jarmila
authors.initials: J
authors.lastname: Vargova
authors.affiliation: Childhood Leukemia Investigation Prague (CLIP), Faculty Hospital Motol Prague, Prague, Czech Republic.
authors.forename: Karel
authors.initials: K
authors.lastname: Fiser
authors.affiliation: Institute of Pathological Physiology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
authors.forename: Dana
authors.initials: D
authors.lastname: Prukova
authors.affiliation: Institute of Pathological Physiology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
authors.forename: Mahmudul
authors.initials: M
authors.lastname: Alam
authors.affiliation: Institute of Pathological Physiology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
authors.forename: Bokang
authors.initials: B
authors.lastname: Calvin Lenyeletse Maswabi
authors.affiliation: Center of Oncocytogenetics, Institute of Clinical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
authors.forename: Kyra
authors.initials: K
authors.lastname: Michalova
authors.affiliation: Center of Oncocytogenetics, Institute of Clinical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Zemanova
authors.affiliation: Synlab Genetics, Department of Cytogenetics, Prague, Czech Republic.
authors.forename: Tereza
authors.initials: T
authors.lastname: Jancuskova
authors.affiliation: Synlab Genetics, Department of Cytogenetics, Prague, Czech Republic.
authors.forename: Sona
authors.initials: S
authors.lastname: Pekova
authors.affiliation: Department of Hematology, Charles University General Hospital Prague, Prague, Czech Republic.
authors.forename: Marek
authors.initials: M
authors.lastname: Trneny
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D002880:Chromosomes, Human, Pair 11; D002883:Chromosomes, Human, Pair 14; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D019656:Loss of Heterozygosity; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020522:Lymphoma, Mantle-Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D008875:Middle Aged; D014178:Translocation, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53
keywords: Richteŕs transformation; chronic lymphocytic leukemia; clonal evolution; mantle cell lymphoma; transforming genes