| Summary: | <p>Abstract</p> <p>Background</p> <p>Chronic myeloid leukaemia (CML) is a haematopoietic stem cell disorder, almost always characterized by the presence of the Philadelphia chromosome (Ph), usually due to t(9;22)(q34;q11) or its variants. The Ph results in the formation of the <it>BCR/ABL1 </it>fusion gene, which is a constitutively activated tyrosine kinase. Around 1% of CML patients appear to have a Ph negative karyotype but carry a cryptic <it>BCR/ABL1 </it>fusion that can be located by fluorescence <it>in situ </it>hybridisation (FISH) at chromosome 22q11, 9q34 or a third chromosome. Here we present FISH mapping data of <it>BCR </it>and <it>ABL1 </it>flanking regions and associated chromosomal rearrangements in 9 Ph negative <it>BCR/ABL1 </it>positive CML patients plus the cell line CML-T1.</p> <p>Results</p> <p><it>BCR/ABL1 </it>was located at 9q34 in 3 patients, 22q11 in 5 patients and CML-T1 and 22p11 in 1 patient. In 3 of 6 cases with the fusion at 22q11 a distal breakpoint cluster was found within a 280 Kb region containing the <it>RAPGEF1 </it>gene, while in another patient and the CML-T1 the distal breakpoint fell within a single BAC clone containing the 3' <it>RXRA </it>gene. Two cases had a duplication of the masked Ph while genomic deletions of the flanking regions were identified in 3 cases. Even more complex rearrangements were found in 3 further cases.</p> <p>Conclusion</p> <p><it>BCR/ABL1 </it>formation resulted from a direct insertion (one step mechanism) in 6 patients and CML-T1, while in 3 patients the fusion gene originated from a sequence of rearrangements (multiple steps). The presence of different rearrangements of both 9q34 and 22q11 regions highlights the genetic heterogeneity of this subgroup of CML. Future studies should be performed to confirm the presence of true breakpoint hot spots and assess their implications in Ph negative <it>BCR/ABL1 </it>positive CML.</p>
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