title: Cryptic BCR-ABL fusion gene as variant rearrangement in chronic myeloid leukemia: molecular cytogenetic characterization and influence on TKIs therapy.
abstract: At diagnosis, about 5% of Chronic Myeloid Leukemia (CML) patients lacks Philadelphia chromosome (Ph), despite the presence of the BCR/ABL rearrangement. Two mechanisms have been proposed about the occurrence of this rearrangement: the first one is a cryptic insertion between chromosomes 9 and 22; the second one involves two sequential translocations: a classic t(9;22) followed by a reverse translocation, which reconstitutes the normal morphology of the partner chromosomes. Out of 398 newly diagnosed CML patients, we selected 12 Ph-negative cases. Six Ph-negative patients treated with tyrosine kinase inhibitors (TKIs) were characterized, in order to study the mechanisms leading to the rearrangement and the eventual correlation with prognosis in treatment with TKIs. FISH analysis revealed cryptic insertion in 5 patients and classic translocation in the last one. In more detail, we observed 4 different patterns of rearrangement, suggesting high genetic heterogeneity of these patients. In our cases, the BCR/ABL rearrangement mapped more frequently on 9q34 region than on 22q11 region, in contrast to previous reports. Four patients, with low Sokal risk, achieved Complete Cytogenetic Response and/or Major Molecular Response after TKIs therapy. Therapy resistance was observed in one patient with duplication of BCR/ABL rearrangement and in another one with high risk. Even if the number patient is inevitably low, we can confirm that the rare Ph-negative CML patients do not constitute a "warning" category, meanwhile the presence of further cytogenetic abnormalities remains an adverse prognostic factor even in TKI era.
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology "L. and A. Seràgnoli", University of Bologna, "S Orsola-Malpighi" University Hospital, Bologna, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Luatti
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology "L. and A. Seràgnoli", University of Bologna, "S Orsola-Malpighi" University Hospital, Bologna, Italy.
authors.forename: Carmen
authors.initials: C
authors.lastname: Baldazzi
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology "L. and A. Seràgnoli", University of Bologna, "S Orsola-Malpighi" University Hospital, Bologna, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Marzocchi
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology "L. and A. Seràgnoli", University of Bologna, "S Orsola-Malpighi" University Hospital, Bologna, Italy.
authors.forename: Gaia
authors.initials: G
authors.lastname: Ameli
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology "L. and A. Seràgnoli", University of Bologna, "S Orsola-Malpighi" University Hospital, Bologna, Italy.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Bochicchio
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology "L. and A. Seràgnoli", University of Bologna, "S Orsola-Malpighi" University Hospital, Bologna, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Soverini
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology "L. and A. Seràgnoli", University of Bologna, "S Orsola-Malpighi" University Hospital, Bologna, Italy.
authors.forename: Fausto
authors.initials: F
authors.lastname: Castagnetti
authors.affiliation: Division of Hematology and Bone Marrow Transplantation, Azienda Ospedaliero-Universitaria di Udine, Udine, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Tiribelli
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology "L. and A. Seràgnoli", University of Bologna, "S Orsola-Malpighi" University Hospital, Bologna, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Gugliotta
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology "L. and A. Seràgnoli", University of Bologna, "S Orsola-Malpighi" University Hospital, Bologna, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Martinelli
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology "L. and A. Seràgnoli", University of Bologna, "S Orsola-Malpighi" University Hospital, Bologna, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Baccarani
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology "L. and A. Seràgnoli", University of Bologna, "S Orsola-Malpighi" University Hospital, Bologna, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Cavo
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology "L. and A. Seràgnoli", University of Bologna, "S Orsola-Malpighi" University Hospital, Bologna, Italy.
authors.forename: Gianantonio
authors.initials: G
authors.lastname: Rosti
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology "L. and A. Seràgnoli", University of Bologna, "S Orsola-Malpighi" University Hospital, Bologna, Italy.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Testoni
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000235:genetics*; D014644:Genetic Variation; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D010677:Philadelphia Chromosome; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D014178:Translocation, Genetic; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D016044:Fusion Proteins, bcr-abl
keywords: BCR/ABL; CML; FISH; Philadelphia chromosome; TKI