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. Issue 10 (2nd August 2016)

• Record Type: Journal Article
• Authors: Klener, Pavel; Fronkova, Eva; Berkova, Adela; Jaksa, Radek; Lhotska, Halka; Forsterova, Kristina; Soukup, Jan; Kulvait, Vojtech; Vargova, Jarmila; Fiser, Karel; Prukova, Dana; Alam, Mahmudul; Calvin Lenyeletse Maswabi, Bokang; Michalova, Kyra; Zemanova, Zuzana; Jancuskova, Tereza; Pekova, Sona; Trneny, Marek
• Is Part Of: International journal of cancer. Volume 139:Issue 10(2016:Nov. 15)
• Page Start: 2252
• Page End: 2260
• Publication Date: 2016-08-02
• Subjects: chronic lymphocytic leukemia -- mantle cell lymphoma -- Richteŕs transformation -- transforming genes -- clonal evolution; Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.30263
• Languages: English
• ISSNs: 0020-7136

Abstract

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. Abstract : What's new? Richter syndrome represents the transformation of chronic lymphocytic leukemia (CLL) into an aggressive lymphoma. Here, the authors describe a CLL patient who developed a clonally‐related highly aggressive pleomorphic variant of mantle cell lymphoma (MCL) following repeated fludarabine‐based therapy for first relapse of CLL. Exome sequencing revealed MCL‐restricted mutations including TP53, CREBBP, NUP214, FUBP1 and SF3B1. Both sequencing and molecular cytogenetic data support the hypothesis of a slow development of the pre‐MCL clone in parallel to CLL over several years, thereby excluding the possibility that the transformation event occurred at the stage of the CLL relapse clone by mere t(11;14)(q13;q32) acquisition.