Research Papers:

Cryptic BCR-ABL fusion gene as variant rearrangement in chronic myeloid leukemia: molecular cytogenetic characterization and influence on TKIs therapy

Simona Luatti _, Carmen Baldazzi, Giulia Marzocchi, Gaia Ameli, Maria Teresa Bochicchio, Simona Soverini, Fausto Castagnetti, Mario Tiribelli, Gabriele Gugliotta, Giovanni Martinelli, Michele Baccarani, Michele Cavo, Gianantonio Rosti and Nicoletta Testoni

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Oncotarget. 2017; 8:29906-29913. https://doi.org/10.18632/oncotarget.15369

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Simona Luatti1, Carmen Baldazzi1, Giulia Marzocchi1, Gaia Ameli1, Maria Teresa Bochicchio1, Simona Soverini1, Fausto Castagnetti1, Mario Tiribelli2, Gabriele Gugliotta1, Giovanni Martinelli1, Michele Baccarani1, Michele Cavo1, Gianantonio Rosti1, Nicoletta Testoni1

1Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology “L. and A. Seràgnoli”, University of Bologna, “S Orsola-Malpighi” University Hospital, Bologna, Italy

2Division of Hematology and Bone Marrow Transplantation, Azienda Ospedaliero-Universitaria di Udine, Udine, Italy

Correspondence to:

Simona Luatti, email: [email protected]

Keywords: CML, BCR/ABL, Philadelphia chromosome, FISH, TKI

Received: September 23, 2016    Accepted: January 16, 2017    Published: February 16, 2017


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.

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