Deletions of the Normal ABL1 at the Non-Translocated Chromosome 9 in CML Associated with TKI Resistance.

Abstract 3254

Poster Board III-1

Chronic myeloid leukaemia (CML) is characterized by the expression of the BCR/ABL1 fusion gene, a constitutively activated tyrosine kinase that commonly results from the formation of the Philadelphia chromosome (Ph) after a t(9;22)(q34;q11) or variant rearrangement. Some 10% to 15% of CML patients present with cryptic deletions adjacent to the translocation breakpoint junction on the derivative chromosome 9. These deletions are believed to occur during the formation of the Ph translocation and are associated with a worse prognosis for CML patients treated with hydroxyurea or interferon. However there is still conflicting data regarding the significance of these deletions in patients receiving imatinib therapy, which appears to overcome the poor prognosis associated with the genome loss. Here we present data of three BCR/ABL1 positive CML patients on tyrosine kinase inhibitors (TKI) who developed therapy resistance. In all patients loss of the ABL1 sequences was identified. Surprisingly, these deletions affected not the ABL1 sequences of the ABL1/BCR fusion on the der(9) chromosome but the normal ABL1 allele on the non- translocated homologue of chromosome 9. This loss was not present at the time of diagnosis but was a new event developed during disease progression and found along with other additional chromosome rearrangements in the BCR/ABL1 positive cells. Bone marrow chromosome suspensions were studied by array comparative genomic hybridization (aCGH) analysis and/or fluorescent in situ hybridization (FISH) using and a range of commercial and bacterial artificial chromosomes (BAC) probes. While one patient carried a large deletion del(9)(q31q34) that spanned several megabases and was detectable by G-banding analysis, the other two patients had small cryptic losses (from 1.8 Mbp to 2.6 Mbp). The loss involved 3' ABL1 sequences in one patient whereas it affected the whole gene in the other two cases. Since the negative control exercised by the normal ABL1 allele over the BCR/ABL1 expression has been documented, the sensitivity to the TKI might be affected in the BCR/ABL1 positive cell clone bearing the genome loss. In summary, we report a new type of ABL1 loss in Ph positive cells - deletions at the 9q34 associated with TKI resistance in CML patients.