Characterisation of the genomic landscape of CRLF2 deregulated acute lymphoblastic leukaemia

Deregulated expression of the type I cytokine receptor, CRLF2 (CRLF2-d), is observed in 5-15% of B-cell precursor acute lymphoblastic leukaemia (BCP-ALL), is associated with activation of the JAK/STAT pathway and has an inferior outcome compared to those with good risk cytogenetics. We aimed to determine the clinical and genetic landscape of CRLF2-d ALL using genomic approaches including karyotyping, fluorescence in situ hybridisation, whole genome and whole exome sequencing. The clinical and demographic features of CRLF2-d patients were characteristic of BCP-ALL. Patients with IGH-CRLF2 were older than those with P2RY8-CRLF2 (4yrs v 14yrs, p<0.001), while the incidence of CRLF2-d among Down syndrome patients was high (31%). CRLF2-d co-occurred with established primary chromosomal rearrangements but the majority (72%) had B-other ALL. The copy number alteration (CNA) profile was similar to B-other ALL, although CRLF2-d patients harboured higher frequencies of IKZF1 (43% v 23%) and BTG1 deletions (15% v 2%). There were differences in the CNA profile between IGH-CRLF2 and P2RY8-CRLF2 patients: deletions of IKZF1 (71% v 33% p<0.001), BTG1 (31% v 9%, p=0.004) and ADD3 (46% v 13%, p=0.008). A novel gene fusion, USP9X-DDX3X was discovered in 18% of CRLF2-d ALL. Pathway analysis of the mutational profile revealed novel involvement of the focal adhesion pathway. In conclusion, CRLF2-d defines a discrete subtype of B-other ALL, characterised by a distinctive profile of cooperating abnormalities, which drive leukaemogenesis in conjunction with CRLF2-d. Although the functional relevance of many of these abnormalities are unknown, they likely activate alternative pathways, which may represent novel therapeutic targets. Affymetrix SNP arrays were performed according to the manufacturer's directions on DNA extracted from cryopreserved diagnostic bone marrow or remission bone marrow. DNA copy number analysis of 26 acute lymphoblastic leukaemia samples (11 diagnostic only, 15 matched diagnostic and remission samples) was perform using the Affymetrix Genome-Wide Human SNP6.0 Array.