title: Implication of the Autologous Immune System in BCR-ABL Transcript Variations in Chronic Myelogenous Leukemia Patients Treated with Imatinib.
abstract: Imatinib and other tyrosine kinase inhibitors (TKI) have improved treatment of chronic myelogenous leukemia (CML); however, most patients are not cured. Deeper mechanistic understanding may improve TKI combination therapies to better control the residual leukemic cell population. In analyzing our patients' data, we found that many patients who otherwise responded well to imatinib therapy still showed variations in their BCR-ABL transcripts. To investigate this phenomenon, we applied a mathematical model that integrates CML and an autologous immune response to the patients' data. We define an immune window or a range of leukemic loads for which the autologous immune system induces an improved response. Our modeling results suggest that, at diagnosis, a patient's leukemic load is able to partially or fully suppress the autologous immune response developed in a majority of patients, toward the CML clone(s). Imatinib therapy drives the leukemic population into the "immune window," allowing the patient's autologous immune cells to expand and eventually mount an efficient recognition of the residual leukemic burden. This response drives the leukemic load below this immune window, allowing the leukemic population to partially recover until another weaker immune response is initiated. Thus, the autologous immune response may explain the oscillations in BCR-ABL transcripts regularly observed in patients on imatinib.
authors.affiliation: Department of Mathematics, University of Maryland, College Park, Maryland.
authors.forename: Geoffrey D
authors.initials: GD
authors.lastname: Clapp
authors.affiliation: Inria, and Université de Lyon, Université Claude Bernard Lyon 1, CNRS UMR 5208, Institut Camille Jordan, Villeurbanne Cedex, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Lepoutre
authors.affiliation: Inria, and Université de Lyon, Université Claude Bernard Lyon 1, CNRS UMR 5208, Institut Camille Jordan, Villeurbanne Cedex, France.
authors.forename: Raouf
authors.initials: R
authors.lastname: El Cheikh
authors.affiliation: Inria, and Université de Lyon, Université Claude Bernard Lyon 1, CNRS UMR 5208, Institut Camille Jordan, Villeurbanne Cedex, France.
authors.forename: Samuel
authors.initials: S
authors.lastname: Bernard
authors.affiliation: Centre Hospitalier Lyon, Sud, Pierre-Bénite France and CRCL, Centre Léon Bérard, Lyon, France.
authors.forename: Jérémy
authors.initials: J
authors.lastname: Ruby
authors.affiliation: Centre Hospitalier Lyon, Sud, Pierre-Bénite France and CRCL, Centre Léon Bérard, Lyon, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Labussière-Wallet
authors.affiliation: Centre Hospitalier Lyon, Sud, Pierre-Bénite France and CRCL, Centre Léon Bérard, Lyon, France.
authors.forename: Franck E
authors.initials: FE
authors.lastname: Nicolini
authors.affiliation: Department of Mathematics and Center for Scientific Computation and Mathematical Modeling (CSCAMM), University of Maryland, College Park, Maryland. dlevy@math.umd.edu.
authors.forename: Doron
authors.initials: D
authors.lastname: Levy
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002454:Cell Differentiation; D002999:Clone Cells / Q000473:pathology; D003198:Computer Simulation; D016044:Fusion Proteins, bcr-abl / Q000096:biosynthesis* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology*; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology* / Q000627:therapeutic use; D007157:Immunologic Surveillance; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism; D008954:Models, Biological; D014411:Neoplastic Stem Cells / Q000276:immunology / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D012074:Remission Induction; D014158:Transcription, Genetic / Q000276:immunology*; D016896:Treatment Outcome; D047368:Tumor Burden
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl