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. 2017 May 2;8(18):29906-29913.
doi: 10.18632/oncotarget.15369.

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

Simona Luatti  1 , Carmen Baldazzi  1 , Giulia Marzocchi  1 , Gaia Ameli  1 , Maria Teresa Bochicchio  1 , Simona Soverini  1 , Fausto Castagnetti  1 , Mario Tiribelli  2 , Gabriele Gugliotta  1 , Giovanni Martinelli  1 , Michele Baccarani  1 , Michele Cavo  1 , Gianantonio Rosti  1 , Nicoletta Testoni  1
Affiliations

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

Simona Luatti et al. Oncotarget. .

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.

Keywords: BCR/ABL; CML; FISH; Philadelphia chromosome; TKI.

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Conflict of interest statement

CONFLICTS OF INTEREST

S.S. received compensation as a consultant for Novartis, Bristol-Myers Squibb and Ariad; F.C. has acted as a consultant for and received honoraria from ARIAD Pharmaceuticals, Bristol-Myers Squibb, Novartis and Pfizer; M.T. has acted as consultant and received honoraria from Novartis, BMS and ARIAD; G.G. has acted as a consultant and received honoraria from Bristol-Myers Squibb and Novartis; G.Martinelli served on the speakers’ bureaus of Novartis, Bristol-Myers Squibb, and Pfizer; M.B. has received honoraria from ARIAD Pharmaceuticals, Bristol-Myers Squibb, Novartis and Pfizer, and served on the speakers’ bureaus of Bristol Myers-Squibb and Novartis; M.C. has received honoraria and has been a member of the advisory board for Celgene, Jansen-Cilagand Novartis; G.R. has acted as a consultant for and received honoraria from ARIAD Pharmaceuticals, Bristol-Myers Squibb, Novartis, Pfizer and Roche, and served on the speakers’ bureaus of Bristol Myers-Squibb and Novartis; the remaining Authors had not relevant conflicts of interest to disclose.

Figures

Figure 1
Figure 1
DCDF FISH analysis showing: A. 1R2G1F signal pattern and the BCR/ABL fusion gene on der(9); B. 1R1G1F signal pattern and the BCR/ABL fusion gene on der(9) C. 2R1G1F signal pattern and the BCR/ABL fusion gene on der(22); D. 1R1G2F signal pattern and the BCR/ABL fusion genes on der(9) and der(22).
Figure 2
Figure 2. DCDF FISH analysis showing 1R1G2F signal pattern and the BCR/ABL fusion genes on both chromosomes 9
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