Common Submicroscopic Genomic Imbalances Accompany the Ph Chromosome at Diagnosis in Chronic Myeloid Leukemia

Despite the presence of a consistent genetic abnormality, CML patients display considerable clinical heterogeneity, the basis of which is poorly understood. We therefore used a novel ultra-high-resolution genomic screening assay to search for additional acquired genomic abnormalities that might explain this clinical heterogeneity and help to assess prognosis for individual patients. Comparative genomic hybridisation (CGH) was performed with a 2.1 million oligonucleotide array on DNA extracted from presentation samples of 20 previously untreated CML patients. Each DNA sample from diagnosis was competitively hybridized against the same patient’s remission sample, which avoided detection of constitutional polymorphic copy number variants (CNVs). For representative copy number aberrations (CNAs) the CGH result was confirmed by fluorescence in situ hybridization or quantitative real-time PCR. All 20 CML patient samples harbored detectable genomic imbalances with a median of 16 CNAs per patient (range: 4–165). Of the 846 CNAs detected 679 (80%) were amplifications and 167 (20%) were deletions. 462 CNAs (55%) involved at least one known gene. The median size of CNAs was 58kb (range 9kb – 12Mb). One hundred and twenty seven different genomic regions were aberrant in 2 or more patients in the cohort. Of these recurrent CNAs, amplifications of the FOXD4L4, MAPK8IP1, DUSP1, PSTPIP1 and PBEF1 genes were among the most frequently detected; they were present in 3, 4, 5, 6 and 15 patients respectively. FOXD4L4 is a myeloid trancription factor previously implicated in leukemogenesis, and PSTPIP1 has been shown to be involved in dephosphorylation of ABL. MAPK81P1 and DUSP1 are both involved in the MAPK pathway, while PBEF1 is known to play a role in the NAD anti-apoptotic pathway. The presence of multiple genomic lesions at diagnosis supports the notion of an increased level of genomic instability in CML cells and raises the possibility that one or more aberrations in addition to BCR-ABL may dictate the CML phenotype. The considerable range in the number of CNAs identified at diagnosis may reflect a differing level of genomic instability in different patients. Furthermore the presence of same genetic imbalance in more than one patient suggests a role for specific genes in addition to BCR-ABL in the pathogenesis or progression of CML.