title: Inter- and intratumoral heterogeneity of BCL2 correlates with IgH expression and prognosis in follicular lymphoma.
abstract: Most follicular lymphomas (FLs) are genetically defined by the t(14;18)(q32;q21) translocation that juxtaposes the BCL2 gene to the immunoglobulin heavy chain (IgH) 3' regulatory regions (IgH-3'RRs). Despite this recurrent translocation, FL cases are heterogeneous in terms of intratumoral clonal diversity for acquired mutations and variations in the tumor microenvironment. Here we describe an additional mechanism that contributes to inter- and intratumoral heterogeneity in FLs. By applying a novel single-molecule RNA fluorescence-based in situ hybridization (FISH) technique to detect mRNA molecules of BCL2 and IgH in single cells, we found marked heterogeneity in the number of BCL2 mRNA transcripts within individual lymphoma cells. Moreover, BCL2 mRNA molecules correlated with IgH mRNA molecules in individual cells both in t(14;18) lymphoma cell lines and in patient samples. Consistently, a strong correlation between BCL2 and IgH protein levels was found in a series of 205 primary FL cases by flow cytometry and immunohistochemistry. Inter- and intratumoral heterogeneity of BCL2 expression determined resistance to drugs commonly used in FL treatment and affected overall survival of FL patients. These data demonstrate that BCL2 and IgH expressions are heterogeneous and coregulated in t(14;18)-translocated cells, and determine the response to therapy in FL patients.
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Barreca
authors.affiliation: 1] Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy [2] Center for Experimental Medicine and Clinical Studies (CERMS), University of Torino, Torino, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Martinengo
authors.affiliation: Department of Medical Sciences, University of Torino, Torino, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Annaratone
authors.affiliation: Department of Clinical and Biological Sciences, University of Torino, Torino, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Righi
authors.affiliation: ASO San Giovanni Battista Hospital, Turin, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Chiappella
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Ladetto
authors.affiliation: ASO San Giovanni Battista Hospital, Turin, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Demurtas
authors.affiliation: ASO San Giovanni Battista Hospital, Turin, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Chiusa
authors.affiliation: ASO San Giovanni Battista Hospital, Turin, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Stacchini
authors.affiliation: 1] Departments of Physics, Massachusetts Institute of Technology, Cambridge, MA, USA [2] Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA [3] Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA [4] Hubrecht Institute-KNAW (Royal Netherlands Academy of Arts and Sciences), Utrecht, The Netherlands [5] University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: N
authors.initials: N
authors.lastname: Crosetto
authors.affiliation: 1] Departments of Physics, Massachusetts Institute of Technology, Cambridge, MA, USA [2] Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA [3] Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA [4] Hubrecht Institute-KNAW (Royal Netherlands Academy of Arts and Sciences), Utrecht, The Netherlands [5] University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: van Oudenaarden
authors.affiliation: 1] Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy [2] Center for Experimental Medicine and Clinical Studies (CERMS), University of Torino, Torino, Italy [3] Department of Pathology, Children's Hospital, Boston, MA, USA [4] Harvard Medical School, Boston, MA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Chiarle
mesh_terms: D045744:Cell Line, Tumor; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics; D002887:Chromosomes, Human, Pair 18 / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000096:biosynthesis / Q000235:genetics; D017404:In Situ Hybridization, Fluorescence; D008224:Lymphoma, Follicular / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D008297:Male; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D014178:Translocation, Genetic
chemical_list: C000595707:BCL2 protein, human; D007143:Immunoglobulin Heavy Chains; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D012334:RNA, Neoplasm